A REVIEW OF THE RANDOMIZED CONTROLLED TRIALS OF TACRINE IN THE TREATMENT OF ALZHEIMERS-DISEASE - METHODOLOGIC CONSIDERATIONS

This review examines the features of the 16 randomized controlled tria ls that have been published on the use of oral tacrine for treating pr obable Alzheimer's disease and explores the methodologic problems asso ciated with these studies. Patient selection using the standard Nation al Institute of Neurological and Communicative Disorders and Stroke/Al zheimer's Disease and Related Disorders Association (NINCDS/ADRDA) cri teria is now a feature of all studies; however, the specificity of the diagnosis, the severity of the dementia, the heterogeneity of the dem entia with respect to disease and patient genotype, and the health sta tus of the patients all are factors that may affect responsiveness to therapy. Most studies use crossover designs; however, because of the p rogressive nature of the disease and the variability in the rate of de cline, parallel group studies over a length of time sufficient to prod uce worsening in disease severity in a placebo group appear to be most suited to detecting clinically relevant therapeutic effects. The clos e relation between doses efficacy, and serious adverse events has been a problem in the tacrine trials, since many studies, titrating to max imum tolerated doses, have used clinically ineffective doses. This pro blem can be circumvented by the use of fixed-dose regimens. Three broa d classes of outcome measures have been used to assess treatment effic acy. 1) performance-based tests of cognitive function, 2) global impre ssions of change on the part of the clinician or care giver, and 3) fu nctional measures of daily living. Including a limited number of each type of measure provides strong evidence of clinically relevant therap eutic benefit; however, more widely accepted and better validated inst ruments need to be developed for all three areas.