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Effectiveness of rivastigmine in Alzheimer's disease

Editor—The clinical relevance of new drugs in Alzheimer's disease has been much debated, and there is little dispute that we need improved trials in the disease.1 Enrolment into trials, however, should be governed by clinical uncertainty.2 
 
Bentham et al criticise recently published studies of rivastigmine and advocate support for studies such as the AD2000 donepezil trial.3 We are concerned that some health authorities in the United Kingdom have stated that reimbursement for donepezil would be made only if patients were randomised into this trial. Presumably, following the lack of participation in the trial by many clinicians in the United Kingdom, the threat of non-reimbursement is an attempt to aid flagging recruitment. 
 
Many clinicians have chosen not to be involved for good reasons. Part of the trial's complicated design seems to attempt to replicate the studies that formed the basis of regulatory approval. The manufacturers already have over 3000 patients with detailed controlled data over six months. The first three months of the trial, before rerandomisation, will not add to this assessment and may confuse rather than enlighten, especially given the use of only the lower, 5 mg dose. The Bristol activities of daily living scale may not have been the optimum choice of primary outcome measure4: we are not aware that it has been shown to be a reliable measure of change over time. Other instruments have been validated longitudinally and used in several hundred patients. 
 
We believe that the Birmingham study is considerably underpowered. On the basis of the dependency scale, we calculate that 4000 patients treated for two years are needed to show with 90% power, and allowing for drop outs, a moderate difference of 20% in dependency for patients with mild to moderate Alzheimer's disease.5 Extending the indications for which donepezil is approved by including vascular dementia is not a problem, but lack of characterisation of the disease at entry to the trial, especially without computerised scanning, is. A negative result is likely and could jeopardise the interpretation of existing data on the beneficial effects of donepezil, and other cholinesterase inhibitors, in Alzheimer's disease. We also query why free drug will not be provided. 
 
The success of large simple trials has been built on the principle of uncertainty by consenting clinicians, not enforcement. Perhaps the authors could address some of these concerns; collectively we could turn this into a valid and relevant study. At present, the situation represents a threat to clinical freedom for many of us who are advocates of large simple trials; we are concerned that undue heed will be taken of the outcome.