Produced by an NHS collaboration of the United Kingdom Medicines Information Pharmacists’ Group and The National Prescribing Centre NEW DRUGS IN CLINICAL DEVELOPMENTAdvance Evaluated Information for Confidential use by NHS Managers and Budget Holders with additional data on health service impact Donepezil in vascular dementia Summary Clinical Impact • Vascular dementia is caused by ischaemic damage to the brain and is associated with cognitive impairment and behavioural changes. Because of its complex nature, diagnosis and treatment are difficult and management options are currently limited. Emphasis is placed on control of vascular risk factors. • Donepezil is a reversible, noncompetitive acetylcholinesterase inhibitor currently licensed for the symptomatic treatment of mild to moderately severe Alzheimer’s disease. Clinical investigations into the use of donepezil in vascular dementia and dementia associated with Parkinson’s disease are currently ongoing. • Published evidence on the use of donepezil in vascular dementia is limited to a single 24-week randomised controlled trial in 595 patients and two small open-label studies: a pilot study in 8 patients and a second trial in 73 patients with multi-infarct dementia. Positive findings included cognitive improvement (especially verbal skills) and functional improvement in activities of daily living (bathing, dressing, toileting, continence and feeding). No behavioural improvement was seen. Financial issues and NHS Impact • Limited trial data means that estimating the financial and NHS impact of donepezil for vascular dementia currently remains speculative. If the two randomised controlled trials (when fully published) produce results which indicate that donepezil has a similar efficacy and safety profile in vascular dementia to that in Alzheimer’s disease, then the service and financial implications may be considerable. • The costs of prescribing acetylcholinesterase inhibitors in England between December 2000 and November 2001 inclusive, was over £6m. Assuming prevalence in the UK of Alzheimer’s disease at 50% and vascular dementia at 20% of total dementia, and similar patterns of disease severity decision making by clinicians, patients and carers in Alzheimer’s disease and vascular dementia, then use of donepezil in vascular dementia would mean an increase in prescribing costs of approximately £2.5m a year or £5,000 per 100,000 population. If donepezil was used in patients with mixed dementia (an unlicensed indication, not currently being investigated by the manufacturer), this figure may be higher. • This estimated impact on prescribing costs may be an underestimate given that the trend in the costs of prescribing acetylcholinesterase inhibitors is increasing. This is in part due to the publication of the NICE Technology Appraisal in January 2001 and in part due to the ongoing development of NHS infrastructure for the assessment, monitoring and support of people with dementia. Date Published: April 2002 Monograph Number: 3/02/03 Region of Origin to whom queries should be directed: West Midlands• Monographs for unlicensed drugs/indications must not • The information contained herein will be superseded in be circulated to prescribers. due course.• Not to be used for commercial purposes. • Copyright UKMIPG 2002.
Donepezil in vascular dementiaAPPROVED NAME Donepezil.BRAND NAME Aricept (Pfizer/Eisai Limited).SYNONYM E2020.PROPOSED INDICATION Dementia associated with vascular disease.PRESENTATION 5mg and 10mg tablets in packs of 28.LICENCE STATUS Licensed in the UK for Alzheimer’s disease in 1997. Trials in vascular dementia ongoing, licence extension application likely to be submitted during 2002.THERAPEUTIC CLASS Drugs for dementia (BNF 4.11).DOSE 5-10mg once daily.COST/COURSE £891-£1248 per patient, per year (MIMS February 2002).ESTIMATED USAGE Eisai estimate approximately 105,000 cases of vascular dementia in England and Wales and an equal number with Lewy body and Parkinson’s disease. NICE estimate 700,000 patients with dementia in England and Wales, of which 400,000 is Alzheimer’s disease. Vascular dementia is likely to make up a substantial majority of the remaining 300,000 cases.TREATMENT ALTERNATIVES Cost of 28 days treatment (MIMS February 2002) Co-dergocrine mesilate 1.5mg three times daily £10.87 Co-dergocrine mesilate 4.5mg once daily £12.94 Co-dergocrine mesilate (dihydroergocornine mesilate/ dihydroergocristine mesilate in equal parts) is the only licensed medication for this condition but it is not widely used. It is rated as being less suitable for prescribing by the BNF.DRUG USAGE The amount spent on co-dergocrine mesilate in England, during the period January 2001 to January 2002 was £45,000.AREAS OF POTENTIAL USE Hospital [Y] Primary Care [Y]. 2
Donepezil in vascular dementiaINTRODUCTION PHARMACOLOGYDementia is one of the most common diseases in Donepezil is a reversible non-competitive cholinesterasethe elderly. It is a major cause of disability and mortality, and inhibitor, which is selective for acetylcholinesterase .is a substantial public health problem [1,2]. It is difficult to Acetylcholinesterase is found in the brain and serumestimate the exact prevalence of vascular dementia as whereas butyrylcholinesterase, the other cholinesterasedifferent diagnostic and pathological criteria have been enzyme, is found mainly in the periphery. The rationale forused across studies . Differential diagnosis is complicated use of donepezil in Alzheimer’s disease is to restoreby the fact that some patients have mixed dementia cholinergic function in the brain following degeneration ofwhere Alzheimer’s disease and cerebrovascular disease cholinergic neurons in the cortex and hippocampus .coexist . A recent review stated that up to 39% of Donepezil offers palliation, not cure, and its efficacy maydementia cases are thought to be vascular in origin, and decrease over time as fewer cholinergic neurones remainan additional 11% to 43% are likely to be mixed . Evidence functionally intact.is emerging from pathological and aetiological studiesof overlap between degenerative and vascular dementiadisorders . Alzheimer’s disease typically affects PHARMACOKINETICSposterior cortical functions e.g. memory, language. Vasculardementia typically presents with subcortical features Donepezil is well absorbed after oral administration withe.g. psychomotor slowing, poor concentration and peak plasma levels seen after 3-4 hours. The mean plasmaapathy . half-life is about 50-70 hours, allowing once daily administration [12,13]. Steady state is achieved in about threeVascular dementia is caused by ischaemic damage to weeks. There are no requirements for dosage modificationthe brain, and is the most preventable form of dementia in the elderly, in renal impairment or in mild to moderateassociated with later life. The location of the brain injury hepatic impairment as clearance of donepezil is not affectedseems to determine, to some extent, the symptoms seen. by these conditions .These include cognitive impairment (e.g. amnesia, aphasia,neglect), behavioural changes or motor-sensory deficits[6,7]. Various authors have observed that vascular EFFICACYdementia is not a single clinical entity and thatpathogenesis is multifactorial. Risk factors may be Published reports of the use of donepezil in vascular dementiaclassified as modifiable (hypertension, hyperglycaemia, are limited to preliminary results of a randomised, placebo-hyperlipidaemia) and non-modifiable (age, race, controlled trial (RCT), available in poster format  andgenetic) [6,7]. two small, open-label studies [15,16]. Full results of the RCT  are due for publication in mid-2002 and a secondBecause of the complex interaction between vascular controlled study is in progress .damage and signs and symptoms, diagnosis can be difficult.Management options are limited, with emphasis being placed Other studies of donepezil in dementia associated withon control of vascular risk factors, particularly those for vascular and Parkinson’s disease are currently ongoing .stroke. Reduction of the risk of recurrent cerebral infarctionsresults in increased cerebral perfusion and stabilisation of Vascular dementiacognitive decline. Several agents have been studied in multi-infarct dementia (a major category of vascular dementia). Results of the first randomised controlled trial of donepezilThese include co-dergocrine and nicergoline (for vasoactive in vascular dementia were published as a conference posterand metabolic activating effects), pentoxifylline and in January 2002 . Six hundred and sixteen patients agedpropentophylline (for haemorrheologic effects), and over 40 years, who satisfied the NINDS-AIREN criteria forpiracetam and its analogues (for enhancement of cerebral probable or possible vascular dementia were enrolled in themetabolism and modulation of neurotransmitter functions). 24-week, double-blind, randomised, placebo-controlledMost of the drugs studied so far have shown only modest study with 595 receiving treatment initially. The NINDS-benefits, which were often not clinically significant . AIREN criteria defines vascular dementia as cognitiveCalcium antagonists (e.g. nimodipine) appear to be useful in decline involving memory loss, as well as impairment in atsubcortical vascular dementia . Of the vasodilator agents, least two other cognitive domains that interfere with activitiesonly the ergoloid agents (hydergine, nicergoline) have shown of daily life. These domains include orientation, attention,modest benefits [8,9]. language-verbal skills, coordination, calculations, executive functions, motor control, functionality, abstraction, andMulticentre trials in vascular dementia of memantine (an judgment. Patients were also required to have neuroimagingantagonist of N-methyl-D-aspartate, NMDA)  and evidence of cerebrovascular disease obtained by a computeddonepezil and galantamine (acetylcholinesterase inhibitors tomography (CT) scan or magnetic resonance imaging (MRI).currently licensed for use in mild to moderately severe Patients with Alzheimer’s disease, mixed dementia orAlzheimer’s disease) are in progress. A dementia prevention dementia caused by conditions not associated withstudy with gingko biloba is also underway . cardiovascular disease were excluded. 3
Donepezil in vascular dementiaTreatment was randomised to donepezil 5mg once daily Modified Hachinski Scale and DSM-111-R criteria for multi-(n=203), donepezil 10mg once daily (n=203) or placebo infarct dementia. Patients satisfying diagnostic criteria for(n=189). For the higher dose donepezil group, treatment was Alzheimer’s disease were excluded. They received donepezilinitiated at 5mg once daily for 28 days and then increased to 5mg daily, increasing to 10mg daily after four weeks, if10mg once daily. Assessments were performed at weeks 6, 12, tolerated (n=62): of these, 43 patients returned to a 5mg dose18 and 24 using Alzheimer’s Disease Assessment Scale - because of side effects. Twelve patients failed to completeCognition Subscale (ADAS-cog), Mini-Mental State the 16-20 week study period .Examination (MMSE), both measures of cognitive functionClinician’s Interview-Based Impression of Change-plus version Clinical impression evaluation used subjective cognitive(CIBIC-plus) — an assessment of global function, and the improvement, MMSE, ADL and Instrumental Activity ofAlzheimer’s Disease Functional Assessment of Change Scale Daily Living (IADL) scales. Behavioural outcomes included(ADFACS) — an assessment of ability to perform basic and depression, agitation, violence, anxiety and paranoidinstrumental activities of daily living (ADLs). thoughts. Functional and overall caregivers’ evaluation were also included. Cognitive improvements, most commonlyWhen examining these results it is important to bear in mind verbal skills and attention, were seen in 31 patients (42%).that they are from a poster presentation and full analysis of Mean MMSE values declined from 14.8 (range 10-24) atthe published RCT is required to confirm them. Efficacy baseline to 12.2 (range 7-23). Functional improvement, mainlyanalyses were performed on the intent-to-treat population in ADL functions rather than IADL functions such as drivingwho received at least one dose of medication and who and shopping, was seen in 32 patients (43.8%). Caregiverprovided data for baseline and at least one other assessment satisfaction was reported for 54 (73.9%) of patients. Again,(n=595). Donepezil treated patients showed significantly ADL type of improvement (bathing, dressing, toileting,greater improvement on the ADAS-cog scale than the continence, feeding) was most associated with carerplacebo group from week 12 onwards (donepezil 10mg satisfaction. Verbal communication was the most noticeablep<0.001 weeks 12-24, donepezil 5mg p<0.001 weeks 12 and cognitive improvement. No behavioural improvement was18, donepezil 5mg p< 0.01 at week 24). The placebo group seen and behavioural deterioration was noted in 16 (21.9%)showed no decline below baseline values during the study. of patients .CIBIC-plus scores at 24 weeks showed significant benefitsin favour of donepezil 10mg daily and donepezil 5mg daily Results of the studies are summarised in Table 1.vs placebo and statistically significant difference at endpoint(10mg p=0.047; 5mg p=0.004 at last observation carried Dementia in Parkinson’s diseaseforward [LOCF]). At week 24, 35% of the higherdose group, 44% of the lower dose group and 26% of the As cognitive impairment may occur in patients withplacebo group showed at least minimal, improvement, but Parkinson’s disease studies are also ongoing in this patientthere was insufficient data to assess what percentage group. One study found the risk of dementia in patients withof patients showed moderate or marked improvement. Parkinson’s disease to be six times higher that of the elderly population . In a randomised placebo-controlled, double-Similar benefit was seen for MMSE values in the donepezil blind, cross-over study, 14 Parkinsonian patients were givengroups versus placebo at 24 weeks (higher dose group: donepezil 5mg daily for 42 days, then 10mg daily or placebop<0.001, lower dose group: p<0.01). Whilst ADFACS scores for two sequential randomised periods of 10 weeks each.showed a progressive decline in the placebo group over the Selection criteria were MMSE scores of 16-26, impairedstudy period, scores were maintained above baseline in memory plus at least one other cognitive impairment occurringpatients treated with donepezil 10mg. Patients treated with at least one year after onset of Parkinson’s disease. Thedonepezil 5mg showed less deterioration than placebo. assessment used MMSE and CIBIC-plus scores. MMSESignificant benefits vs placebo were seen with the donepezil score difference from baseline to week 10 was 2.1 points for10mg daily group at week 12 (p=0.02). donepezil (95% CI: 0.4-3.8 ) and 0.3 for placebo (95% CI: -1.8- 2.8), p=0.013 donepezil vs placebo. Mean CIBIC-plus scoreIn a small, open-label study, eight patients (aged 70-81 years) at week 10 was 3.3 for donepezil and 4.1 for placebo (p=0.034).who met NINDS-AIREN criteria for probable vascular No carry-over or learning effects were detected. Nodementia were given donepezil 5mg once daily for six to worsening of Parkinson’s disease was seen .eight weeks, then 10mg once daily. After six months, themean MMSE score had increased from 20.00 + 3.16 at baselineto 21.40 + 3.25, a non-significant result. The mean Clinical PHARMACOECONOMIC DATADementia Rating decreased from 1.56 + 0.42 to 1.25 + 0.38 :p<0.05) over the same period. Caregivers reported None available.positive results from medication in all eight patients. Patientswere reported to be more engaged in activities and in theirself-care . ADVERSE EFFECTSA second study, also of open-label design, included 73 Donepezil is generally well-tolerated in both short  andpatients aged 67 to 91 years. All patients satisfied the long-term use . Most adverse effects are of mild to 4
Donepezil in vascular dementiamoderate intensity and related to the cholinergic system. if significant cardiovascular disease is present and is judgedThey include; nausea, diarrhoea, vomiting, fatigue and to be causally related to the cognitive impairment [23-26].muscle cramps . Overall incidence of side effects is similarbetween donepezil 5mg daily and placebo, but higher with Dementias should not be regarded as severe forms of athe 10mg daily dose compared with placebo [20,21]. This normal ageing process. However, one study found that 93%higher incidence of adverse effects at the 10mg daily dose of healthy elderly people had abnormalities suggestive oflevel can be reduced by initiating treatment at 5mg daily and vascular origin on brain MRI scans  and minorincreasing to 10mg daily after four to six weeks . cerebrovascular pathology is common in association with other dementias including Alzheimer’s disease .In the study discussed previously, side effects which According to the NINDS-AIREN criteria , a diagnosis ofoccurred more frequently in the treatment groups compared probable vascular dementia is made if dementia (memorywith the placebo group were generally cholinergic in origin impairment plus two other cognitive domains) is associated(e.g. diarrhoea, nausea, leg cramps). The incidence of with focal neurological signs and imaging evidence ofcardiovascular effects such as syncope or hypertension was cerebrovascular disease is present. There must be a temporalsimilar for all groups. Discontinuation rates due to adverse relationship between the onset of the cognitive disturbanceeffects were 16.3% in the donepezil 10mg group, 10.1% in the and the cerebrovascular event.donepezil 5mg group, and 8.8% in the placebo group . Estimates of the prevalence of vascular dementia have variedNo clinically significant effects on laboratory parameters across studies because of methodological differences, butincluding liver function have been seen after long-term use point to vascular dementia being about 20% of the total. In the study of donepezil in multi-infarct dementia , cases of dementia and the second most common dementia12 (16.4%) of the 73 patients withdrew because of side effects after Alzheimer’s disease in Western societies. The(nausea, vomiting, abdominal pain, gastrointestinal bleeding, Alzheimer’s Society estimate vascular dementia to accountdizziness, nightmares, and anorexia and weight loss). Overall, for 20% of all dementia  . NICE have made estimates for40 (46.5%) of patients in this study experienced side effects, the impact of Alzheimer’s disease suggesting that in a PCTmost commonly gastrointestinal upset. of 200,000 people there are likely to be around 1330 cases of Alzheimer’s disease with 798 people with mild to moderate disease . No such estimates are yet available for vascularPRECAUTIONS/CONTRAINDICATIONS dementia.Currently, when prescribing donepezil for the treatment of The onset of vascular dementia is often sudden, with aAlzheimer’s disease, it is recommended that donepezil should transient ischaemic attack (TIA) or a stroke, after which thebe initiated by specialists (including Old Age Psychiatrists, clinical course may be static, remitting or progressive, oftenNeurologists and Care of the Elderly Physicians) . with a fluctuating or stepwise deterioration. However, otherTherapy should only be started if a caregiver is available to patterns of disease such as cognitive impairment of gradualmonitor the drug intake of the patient . Discontinuation onset and slow progression are not uncommon, and theshould be considered when evidence of a therapeutic effect presence of risk factors for cardiovascular disease shouldis no longer present . Co-administration of donepezil alert the clinician to the possibility of vascular dementia.with other acetylcholinesterase inhibitors, agonists or Focal neurological symptoms (such as visual disturbances,antagonists of the cholinergic system should be avoided . brainstem abnormalities, sensory or motor symptoms) and signs (hemiparesis, visual field defects, pseudobulbar palsy,In vitro studies have shown that cytochrome P450 extrapyramidal signs) also increase the probability of aisoenzymes 3A4 and to a minor extent 2D6 are involved in dementia being of vascular origin.the metabolism of donepezil. Drugs inhibiting these enzymese.g. ketoconazole, itraconazole, erythromycin and fluoxetine The cognitive deficits in vascular dementia are multifocalcould affect donepezil metabolism. Enzyme inducers e.g. and therefore more varied than generally seen in Alzheimer’sphenytoin, carbamazepine and alcohol may reduce the levels disease. Memory deficit may not be as marked; discrepanciesof donepezil. Use of donepezil is contra-indicated in pregnant between verbal and non-verbal memory performance arewomen and those patients with a known hypersensitivity to often notable . Other common elements are visuo-spatialthe drug . dysfunction, dysphasia, cognitive slowing and impairment of executive function .EPIDEMIOLOGY AND ESTIMATED COSTS TO THE Longitudinal studies of vascular dementia suggest mortalityHEALTH SERVICE rates and rates of admission to nursing homes for vascular dementia greater than for Alzheimer’s disease. One studyDementia is defined as a multifaceted decline in cognitive reported a five-year mortality rate of 63.6% (compared withfunctioning, causing impaired functioning in daily life. 31.8% for Alzheimer’s disease) and a nursing home admissionImpairment of memory is a necessary aspect, but decline rate of 31.8% (compared with 20.6% for Alzheimer’s disease)in one or more other elements of cognition must also . Currently, the mainstay of treatment is preventativebe demonstrated . Vascular dementia is diagnosed and supportive. Many patients are prescribed aspirin but a 5
Donepezil in vascular dementiaCochrane review has found no evidence to support this There may also be changes in the initial investigation forintervention . However, in a small series of patients with people with dementia that are difficult to predict. A reducedestablished multi-infarct dementia, control of high blood requirement to differentiate between Alzheimer’s disease andpressure, cessation of smoking and use of aspirin improved vascular dementia might mean fewer requests for imaging.or stabilised cognition [34,35]. However, clinicians, patients and carers may feel that, with active treatment as an available option, then investigationFinancial Issues and NHS Impact including imaging may need to be more widely employed to obtain a positive diagnosis, after which an informed decisionLimited trial data means that estimating the financial and about therapy can be made. MRI is the preferredNHS impact of donepezil for vascular dementia currently imaging technique in vascular dementia because of itsremains speculative. Assessment should be interpreted in high sensitivity .the light of the following: The costs of prescribing acetylcholinesterase inhibitors in• Identification of a cohort of people with vascular England between December 2000 and November 2001 dementia is necessarily an inexact science. In a inclusive was over £6m . neuropathological series, the NINDS-AIREN criteria had a sensitivity of 58% and a specificity of 80% and the To estimate the impact of this licence extension we assumed: proportion of cases misclassified as probable vascular dementia was 29%. The criteria successfully excluded • Prevalences in dementia of Alzheimer’s disease at 50% Alzheimer’s disease in 91% of cases and the reliability of and vascular dementia at 20%. the NINDS-AIREN criteria ranges from moderate to substantial [36,37]. • Similar patterns of disease severity in Alzheimer’s disease and vascular dementia.• There is limited published data about the characteristics of the people in the trials. Disease severity is particularly • Similar patterns of decision making by clinicians, patients key, although it is likely, given the requirements of the and carers in vascular dementia and Alzheimer’s disease. trial, setting that people with severe disease would have been excluded. This would result in an increase in prescribing costs of approximately £2.5m a year or £5,000 per 100,000 population• There is limited published data about mean or median if donepezil is used for the treatment of vascular dementia. If absolute improvements in key rating scales, and the range donepezil was used in patients diagnosed with mixed of results obtained from individuals within groups. dementia (an unlicensed indication, not currently being investigated by the company) this figure may be higher.• Consideration of whether statistically significant changes in rating scales indicate clinically significant This estimated impact on prescribing costs is likely to be an improvements for people in dementia therapy trials is underestimate, given that the trend in the costs of prescribing required. acetylcholinesterase inhibitors increased from 10,600 items during December 2000 to February 2001 to 20,600 items during• There are no long-term studies assessing efficacy and September 2001 to November 2001. This in part relates to the safety of donepezil in vascular dementia. publication of the NICE Technology Appraisal in January 2001 and in part to the ongoing development of the NHSIf the two RCTs (when fully published) produce results infrastructure for the assessment, monitoring and supportwhich indicate that donepezil has a similar efficacy of people with dementia.and safety profile in vascular dementia and Alzheimer’sdisease, the service and financial implications may beconsiderable. Clinically, the need to identify people withAlzheimer’s disease as the likely cause for their dementia(and who may benefit from treatment with acetyl-cholinesterase inhibitors) becomes less dominant. Theidentification of people with rarer types of dementia(particularly Lewy body dementia because of the need toavoid neuroleptic prescribing), and the accurate assessmentof disease severity become paramount if donepezil is shownto have benefits for patients who have either Alzheimer’sdisease or vascular dementia. The requirement for monitoringresponse to therapy for the additional cohort of peoplewith vascular dementia receiving active (as opposed tosupportive) therapy would have significant additionalservice implications. 6
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Ref No Study Population Study Design Drug Treatment Outcomes Results 14 595 patients meeting NINDS- Double-blind Donepezil 10mg daily Cognitive function as 24 week results (n=595) AIREN criteria for probable randomised (5mg daily for first 28 assessed by ADAS-cog ADAS-cog significant improvement with donepezil vs or possible vascular placebo- days) and Mini-Mental State placebo: dementia. Study period 24 controlled study. vs Examination (MMSE) scores. donepezil 10mg: p<0.001 weeks. Patients with Donepezil 5mg daily Global function as assessed by donepezil 5mg: p<0.01 Alzheimer’s disease or vs CIBIC-plus scores. Ability to MMSE significant improvement with donepezil vs dementia not associated Placebo. perform activities of daily living placebo: with vascular disease were as assessed by ADFACS donepezil 10mg: p<0.001 excluded. scores. donepezil 5mg: p<0.01 CIBIC-plus significant benefits with donepezil vs placebo: donepezil 10mg: p<0.001 donepezil 5mg: p<0.006 ADFACS mean change from score at endpoint: donepezil 10mg: -0.22 (p=0.02 vs placebo) donepezil 5mg: 0.20 placebo: 0.78 15 Eight patients meeting criteria Open study. Donepezil 5mg daily MMSE Clinical Dementia MMSE: Mean baseline score: for probable vascular for 6-8 weeks, then Rating (CDR). 20.00+3.16 dementia established by 10mg daily. At 6 months: the National Institute of 21.40+3.25 (not significant) Neurological Disorders and Stroke/Association Internationale pour la Recherche et l’Ensignement CDR: Mean baseline score: en Neurosciences 1.56+0.42 International workshop/ At 6 months: American Psychiatric 1.25+0.38 (p<0.05) Association. Study period Carers reported positive results in all 8 cases. six months. 16 73 patients with Multi- Open study. Donepezil 5mg daily for Subjective cognitive Cognitive improvement in 31 of 73 (42.4%). infarct dementia (DSM-III- 4 weeks, then, if improvement. MMSE. Activity MMSE mean baseline score 14.8 and R criteria) for vascular tolerated, 10mg daily. of Daily Living (ADL). after 16 weeks 12.2 (not significant). dementia. Study period 43 patients completed Instrumental Activity of ADL improvements noted in 9.5% overall 16-20 weeks. study on 5mg dose Daily Living (IADL). - 1.2 point deterioration in 16 weeks and 18 on 10mg dose. Behavioural outcomes including IADL improvement in only 1 patient. depression, agitation, Behaviour - no improvement in any patient: violence, anxiety, deterioration in 16 (21.9%). paranoid thoughts. Family satisfaction: positive report in 54 (73.9%). Functional and overall family satisfaction.Table 1: Summary of results from three trials in vascular dementia [14,15,16]. 8