Title: Estimating the benefits and harms of Z-drugs for people with dementia and sleep disorders
Funder: Department of Health and Social Care

Abstract: Background and rationale The class of hypnotic drugs known as Z-drugs (zolpidem, zopiclone and zaleplon; henceforth Zs) are effective for insomnia in the older population but are associated with a spectrum of adverse events including falls, fracture, daytime cognitive impairment and infection. Insomnia and other sleep disturbance is common in people with dementia (PwD) and severely affects quality of life for PwD and carers. Zs are commonly used in dementia as there are few alternative treatments. The nature of the suspected harms of Zs in the general older population suggest that they might be particularly harmful for PwD, but their safety and efficacy has not been evaluated in this group. There is an urgent need to understand the benefits and harms of Zs in PwD, given the importance of Zs in offering respite from sleep disturbance for patients and cares, and the severity of the supposed harms. Study Design We will use existing data to estimate the impact of Z use on adverse events as well as cognitive function, functional ability and quality of life in PwD. Data sources include (i) the Clinical Practice Research Datalink (CPRD which includes data routinely recorded by GPs) and (ii) pooled data from clinical studies including randomised controlled trials (RCTs) and clinical cohorts including people with dementia (PwD). These data sources are complementary and together enable us to fully meet the HTA commissioning brief. First, an inception cohort of around 14,000 PwD and new sleep disturbance will be identified within CPRD. The effect of exposure to Z on the rate of a range of adverse outcomes will be estimated, compared to the effects of other treatments or no treatment. Second, we will harmonise data from around 5,000 PwD recruited to clinical studies. We will use this data to estimate the effect of Z on a range of patient and carer reported outcomes. We will carefully control for potentially confounding covariates and the nature and severity of sleep disturbance. Exposures and comparators We will estimate the effect of Zs compared to other commonly used treatments (in particular benzodiazepines) and to those with no pharmacological treatment. Outcomes Exact outcomes will be prioritised by stakeholders with input from clinicians, care workers and people affected by dementia. Outcomes from CPRD will include falls and fractures, infections, stroke, neuropsychiatric symptoms, healthcare contacts and mortality. Outcomes from RCTs will include changes in cognition and function, changes in sleep disturbance and carer and patient quality of life. Sample size CPRD includes 14,000 PwD with sleep disturbance. Clinical studies together include 5000 PwD, with an estimated prevalence of sleep disturbance in dementia of around 60%. Timelines The project will begin in June 2016 and run for 18 months: Months 1-6. Develop protocols and extract CPRD data; Harmonise and RCT and cohort data. Months 7-18. Analysis and dissemination activity. Expertise Our team includes all necessary expertise: statistics/pharmacoepidemiology (Savva/Richardson/Loke), nursing and dementia care (Arthur), primary care (Steel), pharmacy (Maidment), pharmacology (Loke) and old age psychiatry (Howard/Ballard/Fox). PPI representatives from INSPIRE (a PPI group with a specific interest in mental health and dementia research) will contribute to prioritisation of outcomes, interpretation and dissemination.

Lay abstract: Background More than 800,000 people in the United Kingdom have dementia. Around half of these have trouble sleeping, wake up often and wander during the night, or sleep during the day. This can have a big effect on their health and quality of life, and on their caregivers, other family members or care home residents whose sleep is also disturbed. Powerful sedatives are often given to people with dementia to help them to sleep. But we do not have any evidence from clinical trials about whether sedatives work or are safe in this group. Sedatives have side effects like increasing the risk of falls, confusion, or making memory worse. A group of sedatives called Z-drugs (zolpidem, zopiclone and zaleplon) are often used by people with dementia. They can help people sleep but have side effects and can be addictive. How well they work and what harm they might cause for people with dementia is not known. Aim of the research Our aim is to understand the benefits and harms of using Z-drugs for people with dementia who have trouble sleeping. We will look at whether Z-drugs improve sleep, whether they improve quality of life for people with dementia and their carers and how they affect memory and thinking during the day or other behavioural problems. We will also look at whether people who take Z-drugs fall more often, have more infections or are taken to hospital more often. We will compare Z-drugs to other sleep drugs prescribed to people with dementia, and to people who do not use any sleep medication at all. Design and methods First we will use data from GPs, who record the drugs that they prescribe to people, their illnesses including sleep problems and other health events like falls. This will tell us whether people who take Z-drugs have more accidents, infections or are taken to hospital more often. Next we will use data from clinical studies involving people with dementia. Many studies ask their participants about sleeping problems and about medicines that they use. They also test changes in quality of life, memory and health. This means that data from studies can be reused to answer questions about Z-drugs. We will use these to understand how Z-drugs affect memory and quality of life for patients and carers. Patient and public involvement People with dementia and their carers will join our team to ensure that their experience of using sedatives, and the ways in which people are affected by sleep disorders shape our research. This will ensure the greatest impact where the benefits and harms of these drugs are most keenly felt. They will help us understand what are the most relevant outcomes to examine and what is the best way to present our findings. Dissemination We will present our findings in academic papers, and we will work with the Alzheimer’s Society and PPI representatives to update their guidance on how to manage sleep difficulties for people with dementia and their carers.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL