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


Rivastigmine was effective and safe in Alzheimer disease

ACP J Club. 1999 Sept-Oct;131:34. doi:10.7326/ACPJC-1999-131-2-034

Source Citation

Rösler M, Anand R, Cicin-Sain A, et al. Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomised controlled trial. BMJ. 1999 Mar 6;318:633-40.



What is the effectiveness and safety of rivastigmine in patients with Alzheimer disease?


Randomized, double-blind, placebo-controlled trial with 26-week follow-up.


45 centers in Europe and North America.


725 patients between 45 and 95 years of age (mean age 72, 59% women) who had mild-to-moderate probable Alzheimer-type dementia and scores between 10 and 29 on the Mini-Mental State Examination. Exclusion criteria included life-threatening conditions or use of anticholinergic drugs, acetylcholine precursors, putative memory enhancers, insulin, or psychotropic drugs. Follow-up was 80%.


Patients were allocated to receive either rivastigmine, 1 to 4 mg/d (lower-dose group) (n = 243) or 6 to 12 mg/d (higher-dose group) (n = 243), or placebo (n = 239).

Main outcome measures

Cognitive improvement, progressive deterioration, global function, and treatment-related adverse effects.

Main results

Analysis was by intention to treat. At 26 weeks, more patients in the higher-dose rivastigmine group than in the placebo group had a ≥ 4-point improvement on the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-cog) { P = 0.05}*, a ≥ 10% improvement on the progressive deterioration scale (PDS) (P < 0.01), and an improvement in global function (Clinician Interview-Based Impression of Change [CIBIC] scale scores 1, 2, or 3) (P < 0.001) (Table). Lower-dose rivastigmine improved global function alone better than placebo (P < 0.05) (Table). More patients in the higher-dose group (91%) reported ≥ 1 adverse effects than did those in the lower-dose (71%) { P < 0.001}* or placebo group (72%) { P < 0.001}*. Overall dropout rates were 33% in the higher-dose group, 14% in the lower-dose group, and 13% in the placebo group; more dropouts caused by adverse events occurred in the higher-dose group than in the lower-dose or placebo groups { P < 0.001}*.


Rivastigmine was safe and effective at doses of 6 to 12 mg/d in treating patients with mild to moderate Alzheimer disease.

Source of funding: Novartis Pharma AG.

For correspondence: Professor M. Rösler, Sektion Gerontopsychiatric, Psychiatrische Universitätsklinik, Fuchsleinstrasse 15, D 97080 Würzburg, Germany. FAX 49-931-203-283.

* P values calculated from data in article.

Table. Rivastigmine regimens vs placebo for Alzheimer disease at 26 weeks†

Improvements Dose Rivastigmine Placebo RBI (95% CI) NNT (CI)
Cognition 6 to 12 mg/d 24% 16% 44% (0.051 to 107) 14 (7 to 37067)
Deterioration 6 to 12 mg/d 29% 19% 53% (10 to 113) 10 (6 to 42)
Global function 1 to 4 mg/d 30% 20% 48% (7 to 105) 10 (6 to 57)
6 to 12 mg/d 37% 20% 83% (34 to 150) 6 (4 to 12)

†Abbreviations defined in Glossary; RBI, NNT, and CI calculated from data in article.


This important pharmaceutical company-supported study of rivastigmine is consistent with previous studies because it emphasizes cognitive status outcomes and also assesses global function. Unfortunately, none of the outcome measures is familiar to clinicians and validation data were not provided.

Behavioral disturbances and neuropsychiatric symptoms, often a major concern to caregivers, were not directly assessed. The cognitive improvements with rivastigmine, as with previous studies of donepezil (1) and ginkgo biloba (2), are modest (in this study, a 1.6-point improvement on the ADAS-cog at 26 wk). Clinicians noted small improvements in the CIBIC scale, a measure of global function, and caregivers reported small improvements in the PDS.

A 4-point difference on the ADAS-cog is judged to be clinically relevant. Compared with placebo, only 8% more patients in the higher-dose group showed this change. As the Table indicates, the number needed to treat (NNT) for improvement in global function with the higher dose of rivastigmine was about half the NNT for cognitive improvements. As functional and behavioral changes often have more clinical relevance than cognitive scores, this may mean that fewer patients will need to be treated to achieve a clinically important improvement than the cognitive data suggest. Longer-term studies are needed to clarify this point.

More dropouts caused by adverse events occurred in the higher-dose group than in the lower-dose group. The authors suggest that tolerability could be enhanced by a more gradual titration regimen, but tolerability will likely always be a limitation.

David G. Wilkinson, MD
Moorgreen HospitalSouthampton, England, UK


1. Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease. Donepezil Study Group. Neurology. 1998;50:136-45.

2. Le Bars PL, Katz MM, Berman N, et al. A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo Biloba for dementia. North American EGb Study Group. JAMA. 1997;278:1327-32.