Abstract
Background
Dementia is an age-associated syndrome most commonly due to Alzheimer’s disease (AD) and/or cerebrovascular disease.
Calcium has an important role in regulating brain functions. Calcium ions link membrane excitation to subsequent intracellular molecular responses. Age-associated changes in calcium homoeostasis have possible repercussions on higher cortical functions. Nimodipine is an isopropyl calcium channel blocker which readily crosses the blood-brain barrier. Its primary action is to reduce the number of open calcium channels in cell membranes, thus restricting influx of calcium ions into cells.
The usefulness of nimodipine in patients with Alzheimer’s disease and vascular dementia and unspecified dementia is still controversial. In spite of the uncertainties about its efficacy in dementia, nimodipine is currently frequently prescribed for cognitive impairment and dementia in several continental European countries.
Objectives
To assess the clinical efficacy of nimodipine for the manifestations of dementia, in unclassified disease and in the major subtypes – Alzheimer’s disease, cerebrovascular disease, and mixed Alzheimer’s and cerebrovascular disease.
Search methods
We searched ALOIS – the Cochrane Dementia and Cognitive Improvement Group’s Specialized Register on 26 March 2010 using the term: nimodipine
The search of August 2005 identified two studies which were excluded. The search of January 2008 identified six new studies for consideration, only one met the inclusion criteria for this meta-analysis although the data were difficult to interpret and they were not included in this update (Pantoni 2005). The latest search of March 2010 identified no new studies for inclusion within the review.
Selection criteria
All unconfounded, double-blind, randomized trials in which treatment with nimodipine was administered for more than a day and compared with placebo in patients with dementia, of unclassified type or attributable to Alzheimer’s disease, cerebrovascular disease, or mixed Alzheimer’s and cerebrovascular disease.
Data collection and analysis
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.
Main results
Fifteen trials were included which tested two treatment regimes, 90 and 180 mg/day of nimodipine for 12, 24 weeks and 52 weeks. Two trials included only patients with Alzheimer’s disease (AD), 10 trials included only patients with cerebrovascular dementia (CVD), and three trials included patients with AD, CVD and mixed disease. Available outcome data from nine trials (2492 patients) cover the domains of cognitive function, activities of daily living, global clinical state, safety and tolerability. By pooling available data from all trials, whatever the diagnosis of the patients included, this review found benefit associated with nimodipine (90 mg/day at 12 weeks) compared with placebo on the SCAG scale (WMD -7.59, 95% CI -9.87 to -5.31, P<0.00001), on clinical global impression (WMD -0.87, 95% CI -1.07 to -0.67, P<0.00001) and cognitive function (SMD 0.61, 95% CI 0.42 to 0.81, P<0.00001) but not on scales assessing activities of daily living. When the AD trials and the VD trials were pooled separately, similar significant results were found for the 90 mg/day dose of nimodipine at 12 weeks.
Drop-out rates were low in the trials, affecting similar proportions of treatment and placebo groups. Nimodipine is well tolerated with a low rate of adverse effects similar to that associated with placebo. There were slightly more adverse cerebrovascular events, and adverse events due to blood problems, associated with placebo than with nimodipine, and adverse autonomic events were slightly more common with nimodipine than with placebo.
Authors’ conclusions
Nimodipine can be of some benefit in the treatment of patients with features of dementia due to unclassified disease or to Alzheimer’s disease, cerebrovascular disease, or mixed Alzheimer’s and cerebrovascular disease. It appears to be well tolerated with few side effects. Data were not available from several trials, a total of more than 500 patients. A meta-analysis of individual patient data from all trials is desirable. Dementia is a chronic disorder and the short-term benefits of nimodipine demonstrated in the trials reviewed do not justify its use as a long-term anti-dementia drug. New research must focus on longer term outcomes.
Plain language summary
Evidence of some short-term benefit of nimodipine for people with dementia
The efficacy of nimodipine, a calcium channel blocker, has been tested in randomized controlled trials for the treatment of dementia, particularly Alzheimer’s disease and multi-infarct dementia, the commonest forms of dementia in older people. The rationale for its use is to restrict the influx of calcium ions into neurons, and, by vasodilatation, to improve blood flow to the brain. This review found evidence of some short-term benefit attributable to nimodipine, mainly in measures of cognitive function and global impression, but not in activities on daily living, for patients with degenerative and multi-infarct dementia, and mixed dementia. Nimodipine is well tolerated with a low rate of adverse effects similar to that associated with placebo.
