New Treatments for Vascular Dementia?
New Treatments for Vascular Dementia?
Abstracts & Commentary
Sources: Erkinjuntti T, et al. Lancet. 2002;359:1283-1290; Pratt R, et al. Second International Congress on Vascular Dementia (ICVD), Salzburg, Austria, Jan. 24-27, 2002.
Vascular dementia (VaD) is the second most common cause of dementia after Alzheimer’s disease (AD). VaD is a pathologically heterogeneous disorder encompassing dementia that is temporally associated with single large cerebral infarcts, multiple small infarcts, lacunar infarcts, or leukoariosis. Most therapies have been directed at treating risk factors associated with these processes (eg, hypertension), inhibiting platelet function with aspirin, increasing cerebral blood flow, or ameliorating behavioral sequelae of dementia such as depression or agitation. Two new studies now describe the effects of the cholinesterase inhibitors galantamine and donepezil on cognition, behavior, and function.
Erkinjuntti and colleagues randomized patients with VaD to galantamine (n = 396) or placebo (n = 196) in a multi-center, double-blind study and followed them for 6 months. All patients had dementia of mild-to-moderate severity (Mini-Mental State Exam score 10-25) had radiographic evidence of cerebrovascular disease, and met standard criteria for probable or possible VaD (essentially, dementia with memory loss and impairment in 2 other cognitive domains). Some patients with VaD also met the accepted criteria for possible AD. Data were analyzed with the last observation carried forward on an intention-to-treat basis. Patients who received galantamine (12 mg twice a day) demonstrated a 2.7-point improvement (P < 0.0001) in cognition at 6 months on the cognitive subscale of the AD assessment scale (ADAS-Cog) compared to the group who received placebo. The ADAS-Cog is a 70-point standardized instrument that is used in most AD clinical trials to evaluate cognitive function. Although the study was not powered to perform adequate subgroup analysis, in the group with VaD alone the mean improvement in ADAS-Cog score was 1.9 points (P = 0.06). In the group with mixed dementia (VaD plus AD), the effect was 2.7 points in favor of galantamine (P = 0.0005).
Positive effects were also seen on the clinician’s interview-based impression of change plus caregiver input (CIBIC-plus), a measure of a patient’s overall condition over time that encompasses cognition, behavior, and function. Compared to placebo, more patients who received galantamine demonstrated improvement or no change (74% vs 59%; P = 0.001). Other significant benefits with galantamine included independent measures of functional independence (the disability assessment in dementia) and behavioral symptoms (the Neuropsychiatric Inventory). The rate of withdrawal from the trial due to adverse effects, largely nausea and vomiting, was higher in the galantamine group (20%) than in the placebo group (8%). Erkinjuntti et al attributed the high rate of discontinuation with galantamine to the rapid dose-escalation schedule. The drug has been better tolerated in trials that used a more extended titration of dosage.
Pratt and colleagues presented similar, but limited, findings from a randomized, double-blind, placebo-controlled 24-week trial of donepezil (either 5 or 10 mg/d) in 616 patients with VaD. Patients meeting criteria for probable (76%) or possible (24%) VaD plus radiographic evidence of cerebrovascular disease were studied. In contrast to the galantamine trial, patients with possible AD were excluded. Significant improvement with donepezil treatment compared to placebo was reported on the ADAS-Cog (P < 0.001), as well as on the CIBIC-plus (P = 0.004 for 5 mg donepezil/d and P = 0.047 for 10 mg donepezil/d). Discontinuation rates were 8.8% in the placebo group, 10.1% with 5 mg/d donepezil, and 16.3% with 10 mg/d donepezil.
Commentary
The benefits of cholinesterase inhibitors to treat AD are well established. They are believed to partially compensate for the brain’s deficit of acetylcholine in AD patients by inhibiting the breakdown of the neurotransmitter at central cholinergic synapses. They also might have direct effects on nicotinic receptors. Three of the 4 cholinesterase inhibitors approved by the FDA are in common use: donepezil (Aricept®), rivastigmine (Exelon®), and galantamine (Reminyl®). All 3 drugs given in randomized, placebo-controlled, double-blind clinical trials have had approximately equivalent positive effects on cognition, behavior, and function in patients with AD. Erkinjuntti et al and Pratt et al have now demonstrated therapeutic effects of galantamine and donepezil on cognition and overall condition in patients with VaD that compare in magnitude to those seen in patients with AD. Nausea and loss of appetite are the most common side effects, seen especially at the initiation of treatment. There is a relative contraindication for patients with cardiac conduction abnormalities, a theoretical risk due to potential negative effects from added cholinergic stimulation leading to heart block or bradycardia. This concern may be relevant in the VaD population, which has a higher prevalence of cardiac disease.
It is sometimes difficult to distinguish between VaD and AD. To diagnose VaD in the galantamine study, dementia must have occurred within 3 months of stroke symptoms, appeared abrupt in onset, or progressed in stepwise fashion. Many patients with VaD, either alone or mixed with AD, do not have such clear-cut temporal features. The study by Erkinjuntti et al supports the benefits of galantamine treatment regardless of the exact diagnosis. However, one should note an important distinction between VaD and AD. As might be predicted by the natural course of VaD, patients who received placebo had little change in cognition (ie, the ADAS-Cog score) over 6 months. This contrasted AD in which deterioration occurs due to degenerative progression. Thus, the positive effect of cholinesterase inhibitors on the ADAS-Cog score in patients with VaD might represent an actual improvement in cognition rather than just a stabilization of cognition as in AD.
Patients with AD suffer from a pathologically defined loss of cholinergic neurons in the basal forebrain. No such selective deficit has been documented in VaD. Thus, the mechanism of action of cholinesterase inhibitors in VaD is unclear but may reflect a generalized modulatory effect on cortical and subcortical cholinergic systems. Also, the underlying pathophysiology of VaD is diverse and represents different underlying etiologies (eg, large vessel occlusive disease vs small vessel lipohyalinosis) and lesion sites (eg, single vessel territories vs diffuse subcortical white matter disease). At present, the evidence is inadequate to recommend cholinesterase inhibitors for all patients with VaD. Finally, it may seem easy to dismiss the relatively small numerical improvements seen with cholinesterase inhibitor treatment (eg, 2.7/70 points on the ADAS-Cog). Greater emphasis should be placed on demonstrating effects on maintenance of independent functioning and improvement in quality of life. —Gregg L. Caporaso, Adjunct Clinical Assistant Professor of Neurology, Weill-Cornell Medical College, New York, NY.
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