Determining Drug Exposure Based on Medication Dispensing Data: A Validation Study of Vitamin K Antagonist Treatment Episodes Against INR Records

Background In pharmaco-epidemiological studies using vitamin K antagonist (VKA) exposure, constructing treatment episodes based on dispensed prescriptions is challenging, particularly due to the large variability in therapeutic dose.
Objectives To validate different methods of constructing VKA treatment episodes based on dispensed prescriptions, using VKA exposure based on international normalized ratio (INR) measurements as a reference.
Methods Data from five Dutch anticoagulation clinics were linked to VKA dispensing data from Statistics Netherlands. Three random samples of 10 000 VKA users between 2013 and 2019 were used to compare the construction of VKA treatment episodes based on dispensings, applying fixed or dynamic methods, against the reference of exposure based on INR measurements. A total of 60 different methods were validated by computing the percentage of INR measurements occurring outside dispensing-based VKA treatment episodes, the ratio of VKA-exposed person-time based on dispensings vs. INR measurements, and the number of dispensing-based episodes.
Results Depending on the method used to construct treatment episodes, 14.8%-42.2% of the INR measurements were not covered by a dispensing-based episode. The VKA-exposed person-time ratio ranged between 0.73 and 1.13, and there was substantial variability in the number of dispensing-based episodes. Fixed methods resulted in a lower percentage of INR measurements outside the dispensing-based episodes, a VKA-exposed person-time ratio closer to 1.0, and a lower number of constructed episodes.
Conclusion Fixed methods performed better than dynamic methods when classifying VKA exposure based on dispensing data. Our findings may guide other researchers working with VKA dispensing data, especially when the tablets dispensed or the prescribed dose are unavailable.