Aligning the evidence with practice: NICE guidelines for drug treatment of Alzheimer's disease.

There are an estimated 35.6 million people with dementia worldwide [1]. More than half of these individuals have Alzheimer’s disease (AD), resulting in a progressive decline in cognition, function and communication, together with the frequent occurrence of neuropsychiatric symptoms. In addition to the enormous human costs to the individuals and their families, dementia costs the global economy GB£604 billion a year [1]. There is a pressing clinical and economic need to find treatments that are both effective and cost effective. Cholinesterase inhibitors, licensed in the late 1990s for mild–moderate AD, were the first widely available treatments. These drugs had a significant impact on treatment and care, giving hope to millions of people with AD and resulting in widespread changes in clinical services to facilitate earlier diagnosis and treatment. Whilst the ancillary benefits for the delivery of clinical care are important, the most crucial issue is whether these therapies actually provide an effective pharmacological treatment for people with AD. There are more than 30 randomized controlled trials (RCTs) of the cholinesterase inhibitors donepezil (Aricept), rivastigmine (Exelon) and galantamine (Reminyl) in people with mild–moderate AD [2]. They confer significant benefits in cognition, function and global clinical outcome, with approximately half of the studies demonstrating additional benefits in neuropsychiatric symptoms [3]. These benefits are broadly similar for the different cholinesterase inhibitors. The usual pattern is for mean cognitive scores to improve and remain above pretreatment levels for up to 9 months [2]. The overall magnitude of benefit compared with placebo corresponds to a small–moderate Cohen’s D standardized effect size of approximately 0.4. Four lines of evidence have been put forward to suggest that this is an important and clinically meaningful benefit. First, there is clear benefit for cholinesterase inhibitors with respect to global clinical outcome [3–5]. Second, ‘buying’ patients up to 9 months of improved cognition has to be understood in the context of a disease where life expectancy from diagnosis is between 4 and 5 years [6]. Third, audit studies have demonstrated significant benefits in 40–70% of individuals treated with cholinesterase inhibitors [7]. Fourth, and most important, a pivotal RCT using Goal Attainment Scaling as the primary outcome measure demonstrated significant benefits for the cholinesterase inhibitor galantamine compared with placebo on outcome measures prioritized by the patients themselves [8]. The value of longer-term treatment is less clear, but open-label extension studies and one 2-year RCT provide some Clive Ballard