Current issues of ACP Journal Club are published in Annals of Internal Medicine


High-dose tacrine improved symptoms in patients with Alzheimer disease

ACP J Club. 1994 Sept-Oct;121:37. doi:10.7326/ACPJC-1994-121-2-037

Source Citation

Knapp MJ, Knopman DS, Solomon PR, et al. A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease. JAMA. 1994 Apr 6;271:985-91.



To evaluate the effectiveness and safety of high-dose tacrine hydrochloride taken for 30 weeks in patients with probable Alzheimer disease.


Randomized, double-blind, placebo-controlled trial with 30-week follow-up.


Outpatient clinics at 33 centers.


663 patients (mean age, 73 y; 53% women) with mild-to-moderate probable Alzheimer disease who had symptoms for ≥ 1 year. Exclusion criteria were significant cardiac disease, cerebrovascular disease, diabetes , liver disease, chronic renal insufficiency, or previous exposure to tacrine or its analogs.


Patients were allocated to 1 of 4 groups: Group 1 received placebo (n = 181); group 2 received tacrine, 40 mg/d for 6 weeks, then 80 mg/d for 24 weeks (n = 60); group 3 (n = 174) and group 4 (n = 238) received tacrine, 40 mg/d for 6 weeks, 80 mg/d for 6 weeks, and 120 mg/d for 6 weeks. Group 3 continued on the 120 mg/d dose for the remaining 12 weeks, whereas group 4 was increased to 160 mg/d for the remaining 12 weeks. Medication was administered in divided doses, 4 times daily.

Main Outcome Measures

Clinician Interview-Based Impression (CIBI), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and Final Comprehensive Consensus. Secondary outcomes included the noncognitive component of the ADAS (ADAS-Noncog), ADAS-Total score, Mini-Mental State Examination (MMSE), and the Global Deterioration Scale (GDS).

Main Results

653 patients were included in the intention-to-treat analysis. A dose-response trend (P ≥ 4.0 points compared with 36 patients (20%) in group 1 {CI for the 7% difference, 1% to 15%)*. 43% of patients withdrew because of adverse effects. The 2 most common reasons for withdrawal in patients treated with tacrine were asymptomatic liver aminotransferase elevations (28%) and gastrointestinal complaints (16%).


Tacrine produced dose-related improvements on objective cognitive tests and on clinician-rated global evaluations in patients with mild-to-moderate probable Alzheimer disease.

Source of funding: Warner-Lambert Company.

For article reprint: Dr. M.J. Knapp, Parke-Davis Pharmaceutical Research, 2800 Plymouth Road, Ann Arbor, MI 48106-1047. FAX 313-996-5240.

*Numbers calculated from data in article.


The study by Knapp and colleagues was longer (30 weeks) and used a higher dosage of tacrine (160 mg/d) than previously reported (1). A substantial number of patients receiving tacrine (70% on 160 mg/d and 55% of all treatment groups) were unable to complete the entire 30 weeks because of adverse drug effects, particularly hepatotoxicity and cholinergic-induced side effects. The positive results observed on cognitive tests and on clinician and caregiver evaluations were in the maximally treated groups and were statistically significant when an intention-to-treat analysis was done. As expected, patients receiving placebo had a decline on their ADAS-Cog performance during the 30-week study. The patients studied were an otherwise healthy group, free from other major medical conditions, and none was taking the more commonly prescribed geriatric medications, such as antidepressants or sedatives.

Evaluation of drug efficacy in elderly patients with Alzheimer disease is fraught with difficulties because of the heterogeneity of the population and some variability in the disease process itself. The clinician must still face the daunting decision of proper patient selection and accept the responsibility for weekly laboratory monitoring. Some patients and their families may find the expense of the drug and the monitoring unacceptable (2). Both partners in the evaluation must ultimately accept that the cognitive improvement with tacrine is, at best, modest and plateaus at the maximum dosage. Whether continued benefit will be seen beyond 7.5 months is still unknown.

Charles V. Guida, MD
The Jamaica Hospital Jamaica, New York, USA