ArticlesEfficacy of galantamine in probable vascular dementia and Alzheimer's disease combined with cerebrovascular disease: a randomised trial
Introduction
In Europe, dementia is more common than stroke, in terms of both incidence and prevalence.1, 2, 3 Alzheimer's disease, primarily a neurodegenerative disorder, is the commonest cause of dementia, followed by the vascular dementias.4, 5
Vascular dementias are now known to extend beyond the traditional multi-infarct form. In addition to multiple stroke, the pathophysiology incorporates interactions between vascular processes (different types of cerebrovascular disease and vascular risk factors), changes in the brain (white-matter lesions and atrophy), host factors (age, education), and premorbid cognitive ability.4, 6 The prevalence of mixed vascular dementia, Alzheimer's disease with cerebrovascular disease, has been underestimated, particularly in older populations.7 In addition to simple coexistence, Alzheimer's disease and vascular dementia have a closer association; they share several vascular risk factors (eg, cerebrovascular disease, arterial hypertension) and vascular pathology in the brain (eg, lacunae, white-matter lesions), which relate to the clinical manifestation of dementia.8, 9 They also share common pathogenetic mechanisms such as neurotransmitter abnormalities.10
One of the key symptoms of dementia is cognitive impairment. Whatever the underlying cause of the particular type of dementia, this impairment results from severe deficits in neurotransmission and degeneration of neuronal circuits in the brain. Therefore, a reasonable approach would be to study in other dementias the effects of drugs that have shown therapeutic benefit in Alzheimer's disease. In all cases studied so far, cognitive deficits involve lower than normal nicotinic cholinergic neurotransmission and numbers of nicotinic receptors.
Until now, there has been no widely accepted standard symptomatic treatment for vascular dementia, and management has focused mainly on preventive measures. Current research will improve the options for primary and secondary prevention of dementia4 and offers the promise of symptomatic treatment of the clinical manifestations of cerebrovascular damage. Furthermore, since differentiation between Alzheimer's disease and vascular dementia on clinical grounds can be difficult, a treatment that provides benefits to both groups of patients would be valuable. Treatment could be initiated early, to provide maximum benefit, while the results of diagnostic evaluations are awaited.
Galantamine, which inhibits acetylcholinesterase and modulates nicotinic receptors,11, 12 has shown long-term benefits across several measures of efficacy (cognition, behaviour, and activities of daily living) in patients with dementia of the Alzheimer type.13, 14, 15 To explore further the therapeutic potential of galantamine, we examined its effects in a mixed population of patients diagnosed as having probable vascular dementia or Alzheimer's disease with cerebrovascular disease. Here, we report combined results of galantamine compared with placebo from the complete study population of a 6-month, randomised, placebo-controlled, double-blind study of galantamine. This study will be followed by a 6-month open-label trial, the results of which will be reported separately.
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Patients
Eligible patients met the clinical criteria of probable vascular dementia of the National Institute of Neurological Disorders and Stroke and the Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN) International Workshop (figure 1),16 or possible Alzheimer's disease according to the National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA).17 They also showed
Results
Of the 592 patients who entered the study, 396 were assigned galantamine 24 mg/day and 196 were assigned placebo (figure 2); 74% and 83%, respectively, completed the study.
The two treatment groups were similar in terms of baseline demographic characteristics (table 1). Alzheimer's disease with cerebrovascular disease was diagnosed in 48% of patients in the galantamine group and 50% of those in the placebo group. Probable vascular dementia was present in 43% and 41%, respectively. In each group,
Discussion
In this trial of a cholinergic drug in patients with probable vascular dementia or Alzheimer's disease combined with cerebrovascular disease, galantamine showed significant benefits in cognition, activities of daily living, behaviour, and global function. The broad benefits are desirable in a chronic disease such as dementia, with potential favourable effects on the burden of carers and health-care resources.
The treatment differences observed were of similar size to those seen in galantamine
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