Rivastigmine in AD Table 1 Essential published rivastigmine trials in AD Study design Study duration Intervention and number of Relevant objectives randomized patients Corey-Bloom 1998 RCT, parallel, double- 26 weeks 1. Rivastigmine 1–4 mg: n = 233 ADAS-cog, CIBIC-plus, blind, multicenter 2. Rivastigmine 6–12: n = 231 PDS 3. Placebo: n = 235 Adverse events Forette 1999 RCT, parallel, double- 18 weeks 1. Rivastigmine bid (6–12 mg/d): n = 45 ADAS-cog, CIBIC-plus, blind, multicenter 2. Rivastigmine tid (6–12 mg/d): n = 45 NOSGER Phase II study 3. Placebo: n = 24 Adverse events Rösler 1999 RCT, parallel, double- 26 weeks 1. Rivastigmine 1–4 mg: n = 243 ADAS-cog, CIBIC-plus, blind, multicenter 2. Rivastigmine 6–12 mg: n = 243 PDS 3. Placebo: n = 239 Adverse events Bullock 2005 RCT, parallel, double- 24 months 1. Rivastigmine 3–12 mg: n = 498 SIB blind, multicenter 2. Donepezil 5–10 mg: n = 500 ADCS-ADL, GDS,NPI Adverse events Abbreviations: ADAS-cog,Alzheimer’s Disease Assessment Scale; CIBIC-Plus, Clinician’s Interview Based Impression of Change; GDS, Global Deterioration Scale; NPI, neuropsychiatric inventory; NOSGER, Nurses Observations Scale for Geriatric Patients; PDS, Progressive Deterioration Scale; RCT, randomized controlled trial; b(t)id, 2 (3) times in one day; n, number of treated individuals; SIB, severe impairment battery. better ratings for CIBIC-Plus than placebo, and signiﬁcantly better scores on the ADAS-cog scale, compared with placebo and the 1–4 mg/day group. However, the 1–4 mg/day treatment group did not improve signiﬁcantly over placebo with either assessment tool. These trials and other clinical trials not reported in detail in this review provided evidence for the clinical efﬁcacy of rivastigmine in AD treatment (Spencer and Noble 1998; Rosler et al 1999; Tariot 2001; Wilkinson et al 2002; Ritchie et al 2004; van Dyck 2004; Wilkinson et al 2004; Takeda et al 2006). Side-effects The most common side-effects of rivastigmine, as experienced by patients in clinical studies, were nausea, vomiting, anorexia, dyspepsia, asthenia, and weight loss. These effects were experienced with greater frequency earlier in the treatment. Therefore it is recommended taking the drug with a meal. Side-effects often settle down with time. Long-term administration of rivastigmine in the studies and in the real world Limited data are available on the tolerability and effectiveness of ChEI therapy for periods up to 5 years. But all available data indicate that rivastigmine was well tolerated and efﬁcacious. There is some evidence that early therapy with rivastigmine may confer some beneﬁt in delaying long- term progression of symptoms, as has been suggested by analysis of the combined 26 weeks of double-blind and ﬁrst 26 weeks of open-label data. Throughout the initial 26-week double-blind part, patients receiving placebo steadily deteriorated, while those treated with high-dose rivastigmine were able to maintain their baseline level of performance on the ADAS-Cog. This approximated a delayed-start design for the open-label portion, which demonstrated that patients who started rivastigmine late never “caught up” with patients who had been on high-dose rivastigmine from the beginning of the trial. This suggests a disease-progression-delaying effect of the drug, which may allow this population to maintain their autonomy for a longer period of time. However, it is important to emphasize the limitations of these data. They are retrospective, the sample was small, there were signiﬁcant numbers of drop-outs, and the availability of free rivastigmine ceased with FDA approval that occurred near to the end of the study (Belle et al 2004; Farlow and Lilly 2005). More recent studies have demonstrated that efﬁcacy and patterns of ChEI use are more complex than previously appreciated. Data now strongly support efﬁcacy for ChEI across the progressive stages of AD. Using combined data from three randomized, placebo-controlled rivastigmine trials, Kurz et al found that rivastigmine maintained ADAS-Cog scores at or above placebo levels across mild, moderate, and severe stages, and the beneﬁts of drug therapy were increasingly apparent at more advanced stages as the rate of decline accelerated in the placebo condition (Frankfort et al 2005; Kurz et al 2004). One study on rivastigmine involved 235 patients who were randomized to the study drug or placebo, 187 of whom subsequently crossed over to open-label treatment with rivastigmine (Farlow et al 2001). The study found that placebo patients who progressed faster during the Neuropsychiatric Disease and Treatment 2007:3(2) 213