Effectiveness of rivastigmine in Alzheimer's disease

Editor—Two recent reports on rivastigmine in Alzheimer’s disease1,2 provide further proof that cholinesterase inhibitors produce modest improvements in cognitive testing and in clinical impression of change. The new claim is of improved functionality with rivastigmine, which, if true, would be an important advance in the management of Alzheimer’s disease. Unfortunately, however, these studies do not establish that functional ability is improved. Both studies rated functionality using the progressive deterioration scale, which was developed to assess quality of life not activities of daily living.3 It contains considerable duplication (for example, four questions on handling finances), and only two items relate peripherally to the basic activities of dressing and eating. It cannot be concluded, therefore, that improved scores equate to improved functionality. Moreover, Rosler et al misrepresent the small improvement in progressive deterioration score seen with rivastigmine (2.8 on a 100 point scale) by citing in the discussion that one third of patients taking higher dose rivastigmine attained at least a 10% improvement in score without noting that 20% of placebo patients also improved to this extent. The benefit was actually only 13% (33% v 20%), which is reduced to 10% (29% v 19%) on more appropriate intention to treat analysis. The intention to treat analyses are also potentially biased because of non-random drop outs: 77 (32%) of 243 higher dose rivastigmine patients did not have a 26 week assessment compared with 31 (13%) of the 239 placebo patients. Alzheimer’s disease is progressive and so replacing missing data by carrying forward values obtained earlier in the trial underestimates natural deterioration. No improvements in progressive deterioration score were seen in the lower dose rivastigmine group, which had the same drop out rate as the placebo group. Thus it remains unclear whether cholinesterase inhibitors produce sufficient benefit in Alzheimer’s disease to justify their widespread use. Clearly, any delays in progress to severe dependency or institutionalisation would be worth while both clinically and economically. Improved functionality, fewer neuropsychiatric symptoms, and reduced burden and stress on carers would also be important. But none of these has been reliably established for rivastigmine or donepezil. Longer term placebo controlled trials addressing these outcomes are urgently required.4 One such study, the national AD2000 donepezil trial, has recently opened and already includes 150 patients. To resolve current uncertainties about the best use of cholinergic agents, widespread support—from clinicians and purchasers—for studies such as AD2000 should be encouraged.