Use of antipsychotic drugs and cholinesterase inhibitors and risk of falls and fractures: self-controlled case series

Abstract

Objective: To evaluate the association between the use of antipsychotic drugs and cholinesterase inhibitors and the risk of falls and fractures in elderly patients with major neurocognitive disorders.

Design: Self-controlled case series.

Setting: Taiwan's National Health Insurance Database.

Participants: 15 278 adults, aged ≥65, with newly prescribed antipsychotic drugs and cholinesterase inhibitors, who had an incident fall or fracture between 2006 and 2017. Prescription records of cholinesterase inhibitors confirmed the diagnosis of major neurocognitive disorders; all use of cholinesterase inhibitors was reviewed by experts.

Main outcome measures: Conditional Poisson regression was used to derive incidence rate ratios and 95% confidence intervals for evaluating the risk of falls and fractures for different treatment periods: use of cholinesterase inhibitors alone, antipsychotic drugs alone, and a combination of cholinesterase inhibitors and antipsychotic drugs, compared with the non-treatment period in the same individual. A 14 day pretreatment period was defined before starting the study drugs because of concerns about confounding by indication.

Results: The incidence of falls and fractures per 100 person years was 8.30 (95% confidence interval 8.14 to 8.46) for the non-treatment period, 52.35 (48.46 to 56.47) for the pretreatment period, and 10.55 (9.98 to 11.14), 10.34 (9.80 to 10.89), and 9.41 (8.98 to 9.86) for use of a combination of cholinesterase inhibitors and antipsychotic drugs, antipsychotic drugs alone, and cholinesterase inhibitors alone, respectively. Compared with the non-treatment period, the highest risk of falls and fractures was during the pretreatment period (adjusted incidence rate ratio 6.17, 95% confidence interval 5.69 to 6.69), followed by treatment with the combination of cholinesterase inhibitors and antipsychotic drugs (1.35, 1.26 to 1.45), antipsychotic drugs alone (1.33, 1.24 to 1.43), and cholinesterase inhibitors alone (1.17, 1.10 to 1.24).

Conclusions: The incidence of falls and fractures was high in the pretreatment period, suggesting that factors other than the study drugs, such as underlying diseases, should be taken into consideration when evaluating the association between the risk of falls and fractures and use of cholinesterase inhibitors and antipsychotic drugs. The treatment periods were also associated with a higher risk of falls and fractures compared with the non-treatment period, although the magnitude was much lower than during the pretreatment period. Strategies for prevention and close monitoring of the risk of falls are still necessary until patients regain a more stable physical and mental state.

Fig 1

Flowchart of study population selection

Fig 2

Study scheme and definitions of treatment periods. A three year washout period before the start date was used to exclude patients with a history of falls and fractures. A one year baseline period was defined to assess patients’ baseline covariates. The study was divided into five separate periods: 14 day pretreatment period before the use of drugs, use of cholinesterase inhibitors alone, use of antipsychotic drugs alone, use of a combination of cholinesterase inhibitors and antipsychotic drugs, and non-treatment period, when cholinesterase inhibitors and antipsychotic drugs were not used. A refill noted within 14 days after the end date of the last prescription (that is, 14 day grace period) was considered as a continuation of a previous prescription. ChEI=cholinesterase inhibitor; AP=antipsychotic drug