Using Multiple Medications with Similar Adverse Drug Reactions Can Increase the Likelihood of a Prescribing Cascade: Results from a Cohort Study

Background: A prescribing cascade occurs when a medication (index medication) causes an adverse drug reaction (ADR), which is treated by prescribing additional medication (marker medication). Prescribing cascades are more likely in patients with polypharmacy but few studies have quantified prescribing cascades due to concurrent use of multiple index medications with the same ADR.

Objectives: To assess whether the concurrent use of multiple index medications potentially causing the same ADR increases the likelihood of a related prescribing cascade.

Methods:

Design: A cohort study was conducted to quantify prescribing cascades associated with multiple medications using dispensing data.
Setting: Prescribing cascades identified from literature, assessed as problematic by an expert panel, and for which the ADR was confirmed in Micromedex were included. Dispensing data for adult patients were retrieved from Jan 2015 to December 2020 from a national database including 30% of community pharmacies covering different regions in The Netherlands. People being dispensed both the index and marker medication of a prescribing cascade were included. Prescribing cascades with a significant positive association were grouped on similar ADR-marker medication.
Exposure: For each ADR-marker group, patients were classified into patients using only one index medication (single medication users) and patients concurrently using two or more index medications (multiple medication users).
Main outcome measure: Adjusted sequence ratio (aSR), adjusting for temporal prescribing trends.
Statistical analysis: Prescription sequence symmetry analysis to calculate the aSRs.

Results: A significant positive aSR was found for 41 prescribing cascades, which included six ADR-marker groups with multiple medication users. The aSRs increased from 1.15 for single medication users to 1.61 for multiple medication users for index medication related to the depression-antidepressants prescribing cascade, from 1.98 to 4.02 for parkinsonism-dopaminergics, from 1.44 to 1.74 for urinary incontinence-incontinence medication, from 1.37 to 2.64 for urinary tract infections-antibacterials, and from 1.36 to 2.81 for erectile dysfunction-erectile medication. For the first 4 ADR-marker groups the confidence intervals did not overlap between single and multiple medication users. No increase was observed for the ADR oedema potentially caused by multiple medication and treated with diuretics.

Conclusions: The use of multiple medications potentially causing the same ADR generally increased the likelihood of a prescribing cascade. The additive effect of medications on the occurrence of prescribing cascades is of particular relevance for older people who often use multiple medications.