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Pharmacoepidemiol Drug Saf. 2018 Jul;27(7):815-822. doi: 10.1002/pds.4562. Epub 2018 May 27.

Electronic health record (EHR) based postmarketing surveillance of adverse events associated with pediatric off-label medication use: A case study of short-acting beta-2 agonists and arrhythmias.

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Department of Pediatrics, Critical Care, University of Colorado School of Medicine, Aurora, CO, USA.
Center for Pharmaceutical Outcomes Research, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado School of Medicine, Aurora, CO, USA.
Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Pediatric Research in Office Settings, American Academy of Pediatrics, Itasca, IL, USA.
Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Robert Larner, M.D. College of Medicine, University of Vermont, Burlington, VT, USA.
Department of Pediatrics, Boston University School of Medicine, Boston, MA, USA.



Use electronic health record (EHR) data to (1) estimate the risk of arrhythmia associated with inhaled short-acting beta-2 agonists (SABA) in pediatric patients and (2) determine whether risk varied by on-label versus off-label prescribing.


Retrospective cohort study of 335 041 children ≤18 years using EHR primary care data from 2 pediatric health systems (2011-2013). A series of monthly pseudotrials were created, using propensity score methodology to balance baseline characteristics between SABA-exposed (identified by prescription) and SABA-unexposed children. Association between SABA and subsequent arrhythmia for each health system was estimated through pooled logistic regression with separate estimates for children initiating under and over 4 years old (off-label and on-label, respectively).


Eleven percent of the cohort received a SABA prescription, 57% occurred under the age of 4 years (off-label). During the follow-up period, there were 283 first arrhythmia events, most commonly atrial tachyarrhythmias and premature ventricular/atrial contractions. In 1 health system, adjusted risk for arrhythmia was increased among exposed children (OR 1.89, 95% CI 1.31-2.73) without evidence of interaction between label status and risk. The absolute adjusted rate difference was 3.6/10 000 person-years of SABA exposure. The association between SABA exposure and arrhythmias was less strong in the second system (OR 1.26, 95% CI 0.30-5.33).


Using EHR data, we could estimate the risk of a rare event associated with medication use and determine difference in risk related to on-label versus off-label status. These findings support the value of EHR-based data for postmarketing drug studies in the pediatric population.


arrhythmia; asthma; children; medication safety; pharmacoepidemiology

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