A newly developed method for assessing co-exposure to free dose combinations: a proof-of-concept study using antihypertensive medications in Danish registers

Background: Elevated blood pressure is a major risk factor for severe medical conditions. Adherence to antihypertensive medication, especially in free-dose combinations, poses a significant challenge. This study aims to develop a novel method for assessing co-exposure to free-dose antihypertensive medications using secondary data sources. Methods: A register-based cohort study was conducted on individuals aged 65 years or older in Denmark who initiated antihypertensive therapy from 1996 to 2016 and followed for 730 days from the index date. A new method was developed to assess co-exposure to antihypertensive medications through redeemed prescriptions, treatment episodes, and overlapping medication events. The method's accuracy was evaluated using a random sample of 400 individuals. Results: A total of 1,021,819 individuals were included in the study, with a mean age of 68.8 years, and 53.7% were women. The method achieved 100% accuracy in identifying co-exposure periods. During the early stage of the follow-up (0–180 days), 54.1% of individuals were co-exposed to at least two antihypertensive medications, while 37.5% were co-exposed during the late stage of the follow-up period (181–730 days). The most frequent antihypertensive combinations included bendroflumethiazide and potassium with either amlodipine or enalapril in the early (13.2% and 12.5% of patients, respectively) and late stages (16.9% and 15.0% of patients, respectively). Conclusions: The newly developed method effectively assesses co-exposure to antihypertensive medications, overcoming previous limitations. The findings reveal common co-exposure combinations and evolving trends in antihypertensive medication use among older individuals, reflecting changes in clinical practice and guidelines over two decades.