Background to AD2000

Alzheimer’s disease is, sadly, very common with an estimated 400,000 people affected in the UK alone. There is no cure and patients’ symptoms get steadily worse over time. In 1997, a new kind of drug (called a cholin-esterase inhibitor) was introduced for treatment of the symptoms of early Alzheimer’s. Three cholinesterase inhibitors are now available: donepezil (Aricept®), rivastigmine (Exelon®) and galantamine (Reminyl®). These drugs increase the levels of a chemical called acetylcholine in the brain, which it is believed helps boost brain activity. Clinical trials have shown that scores on memory tests are a little better with the drugs than with placebo (dummy) tablets. But, the differences are small and it has not been proven that the drugs improve symptoms sufficiently to make any real difference in the quality of life of patients or their carers.

The AD2000 Trial

The AD2000 clinical trial was set up, with funding from the NHS, to find out whether donepezil helped patients cope better with day-to-day activities, improved mood and behaviour, made carers’ lives any easier, and whether donepezil treatment allowed patients to live at home for longer. To ensure a fair comparison, neither the patients, their carers or doctors were told whether the patient was taking donepezil or placebo. The patient’s treatment continued as long as doctor and carer thought it to be in the patient’s best interest. The trial opened to recruitment in October 1998. 566 patients with mild to moderate Alzheimer’s disease were entered, over a period of 3 years, from 22 centres across England and Wales. The average age of the patients was 75, with a range from 46 to 93 years.

Results of AD2000

A full report of the study’s findings was published in the Lancet medical journal on June 26th 2004.  These results are summarised below.

Proven benefits of donepezil:

Donepezil produced small improve-ments in tests of memory and in patients’ ability to perform daily activities, similar to those seen in previous trials:

• Patients’ ability to perform activities of daily living was assessed using the Bristol Activities of Daily Living Scale (BADLS). Patients taking donepezil scored, on average, 1•0 points better on the 60-point BADLS test than patients taking placebo over the first 2 years of treatment. This is equivalent to about a 10-week delay in progression of symptoms

• Memory was assessed using a test called the Mini-mental State Examination (MMSE).  Over the first two years of treatment, patients taking donepezil scored, on average, 0•8 points better on the 30-point MMSE scale than those taking placebo.

No proven benefits of donepezil:

But, donepezil did not allow patients to live at home for longer or delay progress of their disability:

• 42% of patients taking donepezil were in permanent care three years after entering the study compared to 44% of patients taking placebo.

• At 3 years, 58% of patients taking donepezil and 59% of patients taking placebo had progressed to a higher level of disability.

And there were no obvious improvement in any other symptoms:

• Taking donepezil did not improve patients’ mood or behaviour.

• Carers of patients taking donepezil had just as high levels of depression and anxiety as carers of patients not taking donepezil.

• Taking donepezil did not reduce the costs of patients’ NHS or social service care requirements.

• Taking donepezil did not reduce the time unpaid carers, e.g. family, friends and neighbours, spent looking after patients.

• A higher dose (10mg per day) of donepezil was no better than 5mg per day on any measures assessed in the trial.

• It was not possible to identify any particular types of patient more likely to benefit from donepezil than other patients.

What do these results mean?

These findings are very disappointing for people with Alzheimer’s disease and their carers. Donepezil treatment does not allow patients to live at home for longer or delay their progress to a higher level of disability. It does not reduce the amount of time carers spend looking after patients, or reduce behavioural problems. Doubling the dose of donepezil to 10mg a day does not achieve better results, and it is not possible to target treatment at groups of patients who are more likely to benefit from donepezil than others. Donepezil does produce small improvements in patient’s scores on memory tests and ability to perform activities of daily living, but it seems unlikely that the changes are big enough to lead to any worthwhile improvement in the patient’s quality of life.

More effective medical and non-medical treatments are needed for Alzheimer’s disease.

Acknowledgements

We thank all of the patients and carers who took part in the AD2000 study without whose help this study would not have been possible. The AD2000 trial would also not have succeeded without the support given to it by the NHS clinicians, nurses, and pharmacists who made up the AD2000 Collaborative Group. We also thank the NHS Executive R&D (West Midlands), who funded the central organisation and the Health Authorities in the West Midlands, East Lancashire, Iechyd Morgannwg, and North Nottingham who paid for the drug costs.

Publication details

AD2000 Collaborative Group. Long-term donepezil treatment in 565 patients with Alzheimer’s disease (AD2000): randomised double-blind trial. Lancet 2004; 363: 2105-2115.