Adverse effects of Z-drugs for sleep disturbance in people living with dementia: a population-based cohort study

Abstract

Background: Sleep disturbance is common in dementia and often treated with Z-drugs (zopiclone, zaleplon, and zolpidem). While some observational studies suggest that Z-drugs are associated with adverse events such as falls and fracture risks in older people, this has not been studied in dementia. Methods: We used data from 27,090 patients diagnosed with dementia between January 2000 and March 2016 from the Clinical Practice Research Datalink linked to Hospital Episodes Statistics data in England. We compared adverse events for 3,532 patients newly prescribed Z-drugs by time-varying dosage to (1) 1,833 non-sedative-users with sleep disturbance, (2) 10,214 non-sedative-users with proximal GP consultation matched on age, sex, and antipsychotic use, and (3) 5,172 patients newly prescribed benzodiazepines. We defined higher dose Z-drugs and benzodiazepines as prescriptions equivalent to ≥7.5mg zopiclone or >5mg diazepam daily. Cox regression was used to estimate hazard ratios (HR) for incident fracture, hip fracture, fall, mortality, acute bacterial infection, ischaemic stroke/transient ischaemic attack, and venous thromboembolism over 2-year follow-up, adjusted for demographic and health related covariates. Results: The mean (SD) age of patients was 83 (7.7) years and 16,802 (62%) were women. Of 3,532 patients prescribed Z-drugs, 584 (17%) were initiated at higher doses. For patients prescribed higher dose Z-drugs relative to non-users with sleep disturbance, the HRs (95% confidence interval) for fractures, hip fractures, falls and ischaemic stroke were 1.67 (1.13-2.46), 1.96 (1.16-3.31), 1.33 (1.06-1.66) and 1.88 (1.14-3.10). We observed similar associations when compared to non-sedative-users with proximal GP consultation. Minimal or inconsistent excess risks were observed at ≤3.75mg zopiclone or equivalent daily, and for mortality, infection, and venous thromboembolism. We observed no differences in adverse events for Z-drugs compared to benzodiazepines, except lower mortality rates with Z-drugs (HR [95% confidence interval] of 0.73 [0.64-0.83]). Conclusions: Higher dose Z-drug use in dementia is associated with increased fracture and stroke risks, similar or greater to that for higher dose benzodiazepines. Higher dose Z-drugs should be avoided, if possible, in people living with dementia, and non-pharmacological alternatives preferentially considered. Prescriptions for higher dose Z-drugs in dementia should be regularly reviewed.