Elsevier

The Lancet Neurology

Volume 6, Issue 6, June 2007, Pages 501-512
The Lancet Neurology

Articles
Effect of rivastigmine on delay to diagnosis of Alzheimer's disease from mild cognitive impairment: the InDDEx study

https://doi.org/10.1016/S1474-4422(07)70109-6Get rights and content

Summary

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.

Introduction

The term mild cognitive impairment (MCI) has emerged as a nosological construct that describes a cognitive state associated with ageing that is abnormal yet not diagnosable as dementia.1 Although proposed criteria and definitions of MCI are still evolving, the most commonly used definition of MCI specifies the following criteria: both subjective and objective impairments in memory, preserved overall cognitive function outside memory, and normal basic activities of daily living.2 This MCI phenotype has been consistently reported to carry an increased risk of progression or conversion to Alzheimer's disease (AD) or dementia.3, 4 The annual rates of progression from MCI to AD or dementia of this clinical phenotype have generally been reported to be 10–15% per year.4, 5, 6 This identification of MCI as a risk state for progression to AD or dementia holds the potential to allow testing of early treatment interventions that might improve cognitive symptoms, slow the rate of symptom progression towards dementia, and even delay the time to diagnosis or prevent AD or dementia.

Pharmacological treatment of the cholinergic dysfunction of AD with cholinesterase inhibitors has been the most widely used for mild and moderate stages of AD, with symptomatic efficacy shown for up to 1 year in placebo-controlled randomised clinical trials.7 Cholinergic abnormalities have been detected in early AD stages,8, 9, 10, 11 including abnormalities in other markers of the cholinergic system, such as signal transduction,12 p75 neurotrophin receptor concentrations,13 and beta-amyloid peptides.14 These abnormalities have triggered interest in investigating the effect of cholinesterase inhibitors on progression to AD and cognitive function in patients with MCI.15, 16, 17, 18

Our aims were to investigate whether rivastigmine delays the time to progression to AD in patients with MCI, and whether rivastigmine benefits cognitive function in patients with MCI.

Section snippets

Patients

A total of 1526 patients were screened for the study. All patients were identified at entry to have MCI operationally defined by having cognitive symptoms, a global clinical dementia rating (CDR) stage of 0·5,19 and a score of less than 9 on the New York University delayed paragraph recall test.20 There was no specification of the onset or course of the presenting cognitive symptoms of MCI. Patients were excluded if they met either the AD diagnostic criteria of the Diagnostic and Statistical

Results

The baseline characteristics of the InDDEx study population are summarised in table 1. Figure 1 shows the flow of patients through the study. Of the 1526 patients screened for this study, 374 (24%) were screening failures, and 134 (9%) were still in active screening when the study was closed to further randomisation. The randomised groups did not differ in demographic characteristics or in their mean baseline scores. Of the full study sample, 500 patients (49·1%) participated in the APOE

Discussion

MCI has been recognised as an at-risk state for progression to dementia, particularly AD. Rates of progression are 10–15% per year in studies of up to 5 years or longer.2, 5, 6 As a result, MCI is a potentially compelling target for therapeutic intervention. To delay the time to develop AD could have significant clinical, economic, and social consequences.

The InDDEx study investigated the effect of rivastigmine over 3–4 years on the rate of progression from MCI to AD, in addition to the effects

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