Nimodipine for primary degenerative, mixed and vascular dementia

Dementia is an age-related condition in which Alzheimer's disease (AD) and cerebrovascular disease account for the bulk of cases. The role played by calcium in regulating brain functions is well known - the calcium ion links membrane excitation to subsequent intracellular enzymatic response. Change in calcium homeostasis is one important effect of aging with repercussions on higher cortical functions. Nimodipine is an isopropyl calcium channel blocker which can easily cross the blood brain barrier. Its primary action is to reduce the number of open channels, thus restricting influx of calcium ions into the cell. The usefulness of nimodipine in patients with Alzheimer's disease and vascular dementia and unspecified dementia is still controversial with mixed results. In spite of the uncertainties about its efficacy in dementia, nimodipine is currently a frequently prescribed drug for cognitive impairment and dementia in several European countries. This review will be conducted in two phases; the current review is based on evidence from published data only. The second phase will be based on individual-patient data analysed centrally and added to this review in due course.

To determine the clinical efficacy of nimodipine for the symptoms of dementia, either unclassified or according to the major subtypes - Alzheimer's disease, vascular, or mixed Alzheimer's and vascular dementia.

The Cochrane Dementia Group Register of Clinical Trials was searched using the terms 'nimodipine' and 'isopropyl (2-methoxy-ethyl) 1,4-dihydro-2, 6-dimethyl-4-(3-nitrophenyl)-3, 5-pyridinedicarboxylate'.

All unconfounded, double-blind, randomised trials in which treatment with nimodipine was administered for more than a day and compared to placebo in patients with dementia, either unclassified or according to the major subtypes - Alzheimer's disease, vascular, or mixed Alzheimer's and vascular dementia.

Data were extracted independently by the reviewers and the odds ratio (95%CI) or the average difference (95%CI) were estimated. Both intention-to-treat and on-treatment results were extracted.

This review produced no clear results. Many of the data published were not capable of being sensibly pooled. The data were compatible with nimodipine producing improvement, no change or even harm for those with Alzheimer's disease, vascular dementia, or mixed Alzheimer's and vascular dementia. It was not possible to use many of the published results in a combined analysis. For measures of overall clinical improvement, the intention-to-treat analysis, based on one study only, failed to detect any difference between nimodipine and placebo (OR 0.53; 95%CI 0.25 - 1.13). An on-treatment analysis, based on one study only, produced a statistically significant difference in favour of nimodipine (SMD 4.4; 95%CI 3.9 - 5.0). For cognitive function, the effect of nimodipine was statistically significantly different from placebo for the Mini Mental State Examination score (0-30; high =good) (SMD 0.9; 95%CI 0.59 - 1.22) and there was a statistically significant effect in favour of treatment for the Wechsler Memory Scale (SMD 0.47; 95%CI 0.17 - 0.77). These analyses were based only on those who completed the study and not intention-to-treat analyses. There were no results presented in a form suitable for pooling for functional autonomy, behaviour, quality of life dependency (eg institutionalization), effect on carer, death, acceptability of treatment (as measured by withdrawal rate, safety (as measured by the incidence of adverse effects, including side effects, leading to withdrawal).

This review provides no convincing evidence that nimodipine is a useful treatment for the symptoms of dementia, either unclassified or according to the major subtypes - Alzheimer's disease, vascular, or mixed Alzheimer's and vascular dementia. However, as so few of the trials presented data in a format suitable for pooling, the results of this review may be modified when further data from all relevant trials are included. There is an urgent need for the independent evaluation of the data already existing in the trials but not accessible through published or grouped data. An independent meta-analysis of the individual patient data is required. Nimodipine cannot be currently recommended in patients with dementia. The results and conclusions of this update are unaltered by further searching as the additional studies do not add any further valid/eligible data.