Alzheimer Disease: Potkin S

Feldman HH, Ferris S, Winblad B, Sfikas N, Mancione L, He Y, Tekin S, Burns A, Cummings J, del Ser T, Inzitari D, Orgogozo JM, Sauer H, Scheltens P, Scarpini E, Herrmann N, Farlow M, Potkin S, Charles HC, Fox NC, Lane R. · Division of Neurology, University of British Columbia Hospital, Vancouver, Canada. · Lancet Neurol. · Pubmed #17509485 No free full text.

Abstract: OBJECTIVE: To assess the effect of rivastigmine in patients with mild cognitive impairment (MCI) on the time to clinical diagnosis of Alzheimer's disease (AD) and the rate of cognitive decline. METHODS: The study was a double-blind, randomised, placebo-controlled trial of up to 48 months. All patients had MCI operationally defined by having cognitive symptoms, a global clinical dementia rating stage of 0.5, a score of less than 9 on the New York University delayed paragraph recall test, and by not meeting the diagnostic criteria for AD. Primary efficacy variables were time to clinical diagnosis of AD, and change in performance on a cognitive test battery. This study is registered with the US National Institutes of Health clinical trials database (ClinicalTrials.gov), number NCT00000174. FINDINGS: Of 1018 study patients enrolled, 508 were randomly assigned to rivastigmine and 510 to placebo; 17.3% of patients on rivastigmine and 21.4% on placebo progressed to AD (hazard ratio 0.85 [95% CI 0.64-1.12]; p=0.225). There was no significant difference between the rivastigmine and placebo groups on the standardised Z score for the cognitive test battery measured as mean change from baseline to endpoint (-0.10 [95% CI -0.63 to 0.44], p=0.726). Serious adverse events were reported by 141 (27.9%) rivastigmine-treated patients and 155 (30.5%) patients on placebo; adverse events of all types were reported by 483 (95.6%) rivastigmine-treated patients and 472 (92.7%) placebo-treated patients. The predominant adverse events were cholinergic: the frequencies of nausea, vomiting, diarrhoea, and dizziness were two to four times higher in the rivastigmine group than in the placebo group. INTERPRETATION: There was no significant benefit of rivastigmine on the progression rate to AD or on cognitive function over 4 years. The overall rate of progression from MCI to AD in this randomised clinical trial was much lower than predicted. Rivastigmine treatment was not associated with any significant safety concerns.

Farlow M, Potkin S, Koumaras B, Veach J, Mirski D. · Department of Neurology, Indiana University School of Medicine, Indianapolis 46202, USA. · Arch Neurol. · Pubmed #12810489 links to  free full text

Abstract: BACKGROUND: Treatment with cholinesterase inhibitors improves cognition in patients with Alzheimer disease (AD). In studies designed with a washout period at the end of the study, after treatment with a cholinesterase inhibitor is discontinued, the cognitive benefits of therapy are no longer apparent following washout. The rivastigmine trials discussed in this article were not designed with a posttreatment washout period at the end of the study. Therefore, to evaluate the effect of discontinuing treatment, we analyzed the retrieved dropout (RDO) population. OBJECTIVE: To evaluate the change in cognition (at week 26 vs baseline) observed in patients from 3 large clinical trials of AD who prematurely discontinued treatment with placebo or rivastigmine.Design and METHODS: Eligible patients with AD (Mini-Mental State Examination [MMSE] score, 10-26, inclusive) were enrolled in 1 of three 26-week, double-blind, placebo-controlled studies (Novartis US Pivotal [dose-range] Trial, US fixed-dose study, and a Global Pivotal [dose-range] Trial) that compared rivastigmine therapy with placebo. Patients who discontinued study participation (for any reason) (considered to be the RDO population) were encouraged to return for their scheduled week 26 efficacy evaluations. Effects on cognition were assessed using the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog). RESULTS: The results for the Novartis US Pivotal Trials and for the 3 studies combined (Novartis studies B352, B351, and B303) are reported. In the US pivotal trial, RDO patients in the 6- to 12-mg/d group had been not receiving the drug (to be called "off drug") for 102 (57.7) days (mean [SD]) compared with 68 (51.7) days in the RDO placebo group. In these RDO analyses, a statistically significantly greater worsening on the ADAS-Cog mean change score was observed in the placebo group (n = 17) compared with the rivastigmine 6- to 12-mg/d group (n = 33) at week 26 (MMSE score, -8.2 vs -3.0; P =.009). In the pooled studies, the mean (SD) number of days off treatment was 95 (52.0) days for the rivastigmine 6- to 12-mg/d group and 66 (52.7) days for the placebo group. The RDO analysis also showed a statistically significantly greater decline in cognitive function as measured by the ADAS-Cog mean change score in the placebo group (n = 38) compared with the rivastigmine 6- to 12-mg/d group (n = 88) at week 26 (MMSE score, -5.69 vs -2.5; P =.004). A significantly greater proportion of patients in the placebo group exhibited at least a 4-point and 7-point worsening in ADAS-Cog scores at week 26 compared with the rivastigmine 6- to 12-mg/d group in both the Novartis US Pivotal Trials (P =.007, P =.009) and the pooled studies (P =.002, P =.017). CONCLUSIONS: After discontinuation of therapy, rivastigmine-treated patients exhibited less deterioration in cognitive function compared with placebo-treated patients. The less severe worsening of cognition after withdrawal of treatment in patients previously treated with rivastigmine suggests an effect on disease progression.