Prescription cascades associated with acetylcholinesterase inhibitors use: a high-throughput sequence symmetry analysis

Journal article

Background:
Acetylcholinesterase inhibitors (AChEIs), are commonly prescribed for dementia and can cause adverse drug events that may lead to new prescriptions, known as prescription cascades. We aimed to identify potential AChEI-induced prescription cascades using high-throughput sequence symmetry analysis (SSA).
Methods:
Patients aged ≥18 years with 365 days of prior observation initiating AChEIs (donepezil, rivastigmine, or galantamine) were identified from the Clinical Practice Research Datalink GOLD (2002–2022). We screened 510 drug classes and 1,213 individual ingredients initiated within ±180 days of AChEI initiation (365 days in sensitivity analyses). Crude and adjusted sequence ratios (ASRs) were calculated, and positive signals were reviewed for clinical plausibility.
Results:
We identified 66,155 AChEI initiators (median age 81 years [IQR 76 - 85]); 62.8% female). Among ATC classes and individual ingredients, 51 and 46 signals were positive with 28 (55%) and 22 (48%) classified as potential prescription cascades after review. Gastrointestinal drugs showed positive signals including antipropulsives (ASR 1.50 [99% CI 1.28 - 1.75]), loperamide (ASR 1.52 [1.30 - 1.77]) and cyclizine (ASR 2.10 [1.72 - 2.59]). Positive signals were also observed nervous system drugs such as benzodiazepine derivatives (ASR 1.83 [1.55 - 2.16]) and respiratory drugs including corticosteroids (ASR 1.66 [1.33 - 2.08]) and glucocorticoids (ASR 1.54 [1.30 - 1.83]). Most positive signals remained in sensitivity analysis.
Conclusions:
These findings suggest potential AChEI-related prescription cascades consistent with gastrointestinal, neuropsychiatric, dermatological, and respiratory adverse effects. While findings require further validation, this study demonstrates the utility of high-throughput signal detection to support pharmacovigilance in high-risk populations.

Authors: Newby, D; Bobba, SS; Raventós, B; Rowlands, E; Chen, X

• Publication status: Accepted
• Peer review status: Peer reviewed
• Publisher: Oxford University Press
• Journal: Age and Ageing
• Acceptance date: 2026-05-18
• EISSN: 1468-2834
• ISSN: 0002-0729
• Language: English
• Keywords: prescription cascade; sequence symmetry analysis; adverse drug events; acetylcholinesterase inhibitors; pharmacovigilance