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The long-term efficacy and tolerability of donepezil in patients with vascular dementia

The long-term efficacy and tolerability of donepezil inpatients with vascular dementia David Wilkinson1, Gustavo Ro´man2, Stephen Salloway3, Jane Hecker4, Karyn Boundy5, Dinesh Kumar6,Holly Posner7 and Rachel Schindler7 1Memory Assessment and Research Centre, Moorgreen Hospital, Southampton, UK 2University of Texas Medical School at San Antonio, San Antonio, TX, USA 3Memory and Aging Program, Butler Hospital, Providence, RI, USA 4Memory Disorders Study Unit, Repatriation General Hospital, Daw Park, Australia 5Department of Neurology, Queen Elizabeth Hospital, Woodville, Australia 6Eisai Inc., Woodcliff Lake, NJ, USA 7Pfizer Inc., New York, NY, USA Correspondence to: D. Wilkinson, E-mail: [email protected] Objective: To determine the long-term tolerability and efficacy of donepezil in patients with vasculardementia (VaD).
Methods: International, multicentre, open-label, 30-week extension study of two 24-week, randomised,double-blind, placebo-controlled studies. Participants were ambulatory adults (59% female; mean age,74.7
0.3) with a diagnosis of possible or probable VaD and without a diagnosis of Alzheimer's disease,who were medically stable and had completed one of two double-blind studies. All patients receiveddonepezil 5 mg/day for the first 6 weeks, then 10 mg/day (clinician approval required). Assessments wereperformed at week 6 and every 12 weeks thereafter. The main outcome measure was the Alzheimer'sdisease Assessment Scale-cognitive subscale (ADAS-cog). Safety/tolerability measures included adverseevents (AEs) and physical and laboratory evaluations.
Results: Of 1219 eligible patients, 885 (72.6%) were enrolled, of which 707 (79.9%) completed the study;127 (14.4%) patients discontinued due to AEs. A mean reduction (0.6–1.15 points) from double-blindstudy baseline score to week 54 (end of open-label study) on the ADAS-cog was observed for patientswho received donepezil continuously for 54 weeks. ADAS-cog scores remained stable in the group thatinitiated donepezil treatment during the extension study. Most common donepezil-related AEs werenausea (occurring in 5.3%) and diarrhoea (8.8%); no unexpected AEs attributable to donepezil occurred.
Conclusion: These data suggest that donepezil improves cognition for up to 54 weeks in patients withVaD. Patients initiating donepezil in this extension study did not perform as well on the primaryoutcome measure as those initiating donepezil in the double-blind study. Copyright # 2009 John Wiley& Sons, Ltd.
Key words: vascular dementia; donepezil; cholinesterase inhibitor; long-term trial; safety; tolerability; efficacyHistory: Received 20 January 2009; Accepted 21 May 2009; Published online 21 July 2009 in Wiley InterScience(www.interscience.wiley.com).
DOI: 10.1002/gps.2340 throughout the world, there is currently no approvedtherapy for the symptomatic treatment of VaD (Doody Vascular dementia (VaD), one of the most common et al., 2001b), and treatment strategies generally focus forms of dementia (Dubois and Hebert, 2001), results on the control of underlying cardiovascular risk factors from ischaemic injury to brain regions serving such as the treatment of hypertension, correction of memory, cognition and behaviour. In many countries arrhythmias, smoking cessation, management of Copyright # 2009 John Wiley & Sons, Ltd.
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hyperlipidaemia and control of metabolic disorders evaluable patients entering the additional 36-week such as diabetes.
extension phase ( 77 patients per original treatment Given that brain lesions in patients with VaD may group), as well as the potential for selection bias, produce cholinergic dysfunction similar to that seen in efficacy data beyond the original 30-week extension patients with Alzheimer's disease (AD) (Tohgi et al., were not statistically viable and are not presented in the 1996), donepezil, a cholinesterase inhibitor (ChEI) current report. Safety findings from the additional 36- approved for the treatment of AD, was investigated for week extension are reported.
the treatment of VaD. There have been two published24-week, double-blind, placebo-controlled trials ofdonepezil in patients with possible or probable VaD Study entry criteria (Black et al., 2003; Wilkinson et al., 2003), diagnosedclinically and radiologically using NINDS-AIREN All patients who completed the double-blind studies criteria (Roman et al., 2005). A combined analysis were eligible for entry into the open-label study. Entry of these studies (N ¼ 1219) showed that donepezil criteria for the double-blind studies have been des- provided significant improvements at study end cribed previously (Black et al., 2003; Wilkinson et al., compared with placebo for cognition at both 5 and 2003; Roman et al., 2005). Briefly, men and women 10 mg/day doses, and for global function at the 5 mg/ aged at least 40 years with a diagnosis of probable or day dose; donepezil was also well tolerated (Roman possible VaD of at least 3 months' duration, Mini- et al., 2005). A third, currently unpublished, trial of Mental State Examination (MMSE) scores between 10 donepezil for VaD has been conducted, which was very and 26, and with clinical and radiological evidence of similar in scope and structure to the two published cerebrovascular disease were included. Patients with trials, except that screening computed tomography or hypertension, diabetes, cardiac disease or stroke were magnetic resonance imaging scans were reviewed included provided these conditions had been stable for centrally (Roman et al., 2006). As a result of available at least 3 months. Patients with AD or other trial data, donepezil is now licensed for the treatment neurodegenerative disorders were excluded, as were of VaD in Romania, India, South Korea, Thailand, those with major psychiatric disorders or a history of Vietnam, New Zealand and the Philippines.
drug or alcohol abuse. Most concomitant medications The objective of the current study, an open-label were permitted during the study, with the exception of extension of the original double-blind studies (Black other ChEIs and anticholinergics.
et al., 2003; Wilkinson et al., 2003), was to determine All patients (or their legal representative) and their the long-term safety and sustainability of efficacy in caregivers provided voluntary, written informed con- donepezil-treated patients, and to compare the effect of sent for participation in the study. This study was a delayed start to therapy in the placebo patients with conducted in accordance with the ethical principles of effects in patients continually treated with donepezil.
the Declaration of Helsinki, as amended, and inaccordance with local laws and regulations, whicheverafforded the greater protection for the participant.
In this open-label extension, all patients received This was an open-label, 30-week extension study of two donepezil 5 mg/day for the first 6 weeks and 10 mg/day 24-week, randomised, double-blind, placebo-con- thereafter, if approved by a clinician (irrespective of trolled, parallel-group studies in patients with possible their assigned group during the double-blind studies), or probable VaD. The study designs and results for the for a total of 30 weeks. Patients were assessed at week 6 original trials have been published previously (Black and thereafter at 12-week intervals. In the subset of et al., 2003; Wilkinson et al., 2003). Study sites— patients participating in the additional study exten- conducted at 100 sites in the US, UK and Europe. For a sion, donepezil was continued at the same dosage and subset of sites in the United Kingdom, Ireland, assessments were performed at weeks 42, 54 and 66.
Germany and Australia, the study was extended for Vital signs and adverse events (AEs) were monitored at an additional 36 weeks (total extension of 66 weeks); each assessment. A physical and neurological examina- this was for investigators who specifically made the tion was also conducted and laboratory tests (clinical request for their patient(s). Due to a small number of chemistry, haematology and urinalysis) performed.
Copyright # 2009 John Wiley & Sons, Ltd.
Int J Geriatr Psychiatry 2010; 25: 305–313.
Long-term use of donepezil for vascular dementia study withdrawal were cerebrovascular accident (4[1.3%] placebo and 10 [1.7%] donepezil patients), The primary efficacy measure was the Alzheimer's asthenia (four [1.3%] placebo and six [1.0%] donepezil disease Assessment Scale- cognitive subscale (ADAS- patients) and nausea (five [1.7%] placebo and four cog), a measure of cognitive function. Secondary [0.7%] donepezil patients). All other AEs that led to efficacy outcome measures were the Clinical Dementia study discontinuation occurred in less than 1% of Rating-Sum of the Boxes (CDR-SB), a measure of overall disease severity; the MMSE, a second measureof cognitive function; and the Alzheimer's DiseaseFunctional Assessment and Change Scale (ADFACS), a Patient characteristics functional test assessing the patient's ability to performinstrumental activities of daily living (ADLs) and basic No significant differences were found in the baseline ADLs. Safety results were reported for all patients who characteristics of the patients enrolled in this open- received open-label treatment.
label study (sex, race, mean age, dementia severity)when compared with those of the initial double-blindstudies total cohort. Moreover, demographic charac- Statistical analysis teristics were similar regardless of original treatmentgroup (Table 1). Baseline characteristics of the patients Efficacy analyses were performed on observed cases up enrolled in the double-blind trials have been described to week 30 of the open-label treatment (54 weeks since previously (Roman et al., 2005).
the start of the double-blind studies) and summarised During the 30-week open-label phase, 111 patients using descriptive statistics. Results of outcome (12.5%) remained on the 5 mg/day dose, 78 patients measures were presented as mean change from the (8.8%) had their dose increased to 10 mg/day but then baseline score. Statistical analyses were conducted returned to 5 mg/day and 696 (78.6%) patients using analysis of covariance for the ADAS-cog. All escalated to 10 mg/day donepezil and remained at this patients randomised into the open-label extension phase of the study were included in the safety analysis.
Nearly all patients (99.9%) took at least one concomitant medication during the study. Theseincluded antithrombotic agents (85.4% of the total population); vitamins (42.8%); agents acting on therenin–angiotensin system (36.6%); psychoanaleptics, Patient disposition including hypnotics, antidepressants and tranquillisers(38.2%) and serum lipid-reducing agents (31.4%).
Of the 1219 patients enrolled in the two double-blindstudies, 885 (72.6%) continued into the open-labelphase. In total, 707 (79.9%) of these 885 patients completed the 30-week open-label extension. A subsetof 227 (32.1%) patients continued into the additional Cognitive function. Results for the primary outcome extension phase, of whom, 194 (85.5%) completed the measure, the ADAS-cog, showed a mean change from additional 36 weeks (Figure 1).
double-blind study baseline score to week 54 (24 weeks A higher proportion of patients randomised to the double-blind plus 30 weeks open-label) of between placebo group during the original double-blind phase 0.6 and 1.15 points for patients who had received discontinued during the 30-week open-label phase donepezil at either dose for the entire 54 weeks (23.6%) compared with the two donepezil groups (Figure 2A). The mean ADAS-cog score for all the (19.8 and 16.7% of patients from the original 5 and donepezil-treated patients who elected to go into the 10 mg/day donepezil groups, respectively). During the open-label study improved over baseline during 30-week open-label phase, a total of 108 (12.2%) the double-blind trials and remained above baseline subjects discontinued prematurely due to AEs: 43 for the entire open-label phase of the study. This (39.8%) originally randomised to placebo, 36 (33.3%) improvement was observed regardless of the initial to 5 mg/day donepezil and 29 (26.9%) to 10 mg/day randomised dosage (5 or 10 mg of donepezil) during donepezil. During the additional 36-week extension, the double-blind phase (Figure 2A).
19 (8.4%) of the subset of 227 patients withdrew due to The initiation of donepezil treatment in patients AEs. The most common individual AEs resulting in who had been randomised to receive placebo in the Copyright # 2009 John Wiley & Sons, Ltd.
Int J Geriatr Psychiatry 2010; 25: 305–313.

D. Wilkinson et al.
Figure 1 Patient disposition.
double-blind trials and who elected to enter the open- relative to placebo at the end of the double-blind label phase produced no significant improvement in studies and remained improved relative to baseline their ADAS-cog scores, but their scores did remain during the open-label study (Figure 2B). Patients in the stable, close to their baseline values throughout the delayed start group showed an ameliorated response additional 30 weeks of treatment (Figure 2A).
with a smaller initial improvement, which was The MMSE score in both the 5 and 10 mg/day maintained above baseline for a shorter time donepezil treatment groups was significantly improved (Figure 2B).
Table 1 Patient demographics of the open-label phase Treatment in double-blind phase Donepezil 5 mg/day n ¼ 303 Donepezil 10 mg/day n ¼ 281 Male patients (%) Mean ADAS-cog score (SE) Mean MMSE score (SE) Copyright # 2009 John Wiley & Sons, Ltd.
Int J Geriatr Psychiatry 2010; 25: 305–313.
Long-term use of donepezil for vascular dementia Figure 2 (A) Mean change from baseline ADAS-cog scores during double-blind and open-label treatment. (B) Mean change from baseline MMSE scoresduring double-blind and open-label treatment. (C) Mean change from baseline CDR-SB scores during double-blind and open-label treatment. (D) Meanchange from baseline ADFACS scores during double-blind and open-label treatment.
Dosages in figure keys correspond to dosing schedule during double-blind phase only. During the open label extension, all patients received donepezil5 mg/day for the first 6 weeks and thereafter 10 mg/day, if approved by a clinician (76.6% of patients remained at 10 mg/day through study completion).
ol ¼ open label.
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Figure 2 (Continued).
Global function. Scores on the CDR-SB, which label; Figure 2C). As with the ADAS-cog, patients improved from baseline during the double-blind phase randomised to the delayed start group did not for both the 5 and 10 mg/day donepezil groups, experience an improvement in their CDR-SB scores remained improved relative to the double-blind study following the initiation of donepezil treatment in the baseline for 42 weeks of treatment (18 weeks open- open-label phase; however, CDR-SB scores were stable Copyright # 2009 John Wiley & Sons, Ltd.
Int J Geriatr Psychiatry 2010; 25: 305–313.
Long-term use of donepezil for vascular dementia during the 30 weeks of open-label treatment. At the placebo patients (28.9% vs. 25.6%, respectively). Of the end of the extension phase, there were no notable cardiovascular events recorded during this study, differences between the treatment groups.
hypertension (6.3% of all patients) and stroke Although there was no significant difference (4.7%) were the most common. There were 29 deaths between the groups on the ADFACS scale at endpoint, during the study or within 4 weeks of treatment there was a trend suggesting that patients who had been discontinuation: 7 (2.3%) among patients originally randomised to 10 mg/day donepezil during the randomised to placebo and 22 (3.8%) among patients double-blind part of the study declined less during originally randomised to donepezil in the double-blind the open-label phase compared with either those studies. The most common causes of death were receiving donepezil 5 mg/day or the delayed start group cerebrovascular accident, myocardial infarction and (Figure 2D).
malignancy. There were four deaths that investigatorsattributed possibly to study medication: of these, twopatients died of a cardiovascular accident, one from sepsis and one from multisystem failure.
Serious AEs were reported for 228 patients. The Donepezil was well tolerated. Most AEs were mild to most common were cerebrovascular accident (4.7%) moderate in intensity. No new or unexpected AEs and accidental injury (2.1%). There were no clinically attributable to donepezil emerged during long-term meaningful changes in clinical laboratory values, vital treatment. The AEs that occurred during open-label signs, physical examination findings or electrocardio- treatment were the same as those observed during the gram status during the study.
double-blind studies and they occurred with approxi-mately the same frequency in both phases, with 87.6%of patients in the open-label study and 90.2% of patients in the double-blind studies reporting one ormore AE. The only AEs that occurred in more than Improvements in cognitive function in patients with 10% of patients were diarrhoea (12.8%), accidental VaD gained during the 24-week double-blind treat- injury (12.5%) and infection (11.3%) (Table 2). AEs ment with donepezil were maintained above baseline judged to be related to donepezil treatment resulted during a further 30 weeks of open-label treatment.
from expected cholinergic effects, most commonly Patients receiving donepezil (either dose) for 54 weeks nausea (occurring in 5.3% of all patients) and had an improvement in their ADAS-cog score of up to diarrhoea (occurring in 8.8% of all patients). All other approximately one point from their baseline score, drug-related treatment-emergent signs and symptoms suggesting that continuous treatment with donepezil occurred in less than 5% of the study population.
improves and sustains cognitive benefit for at least a Treatment-emergent AEs related to the cardiovas- year. Interestingly, although patients receiving 10 mg/ cular system occurred at a similar rate in treated and day donepezil initially did better than those patients Table 2 Incidence of most commonly occurring TESS (occurring in 5% of patients) during the open-label phase No. (%) of patients experiencing TESS Treatment in double-blind phasea Donepezil 5 or 10 mg/day n ¼ 584 Accidental injury Cardiovascular system TESS ¼ treatment emergent signs and symptoms.
aDosing during double-blind phase only. During the open label extension, all patients received donepezil 5 mg/day for the first 6 weeks and thereafter10 mg/day, if approved by a clinician (76.6% of patients remained at 10 mg/day through study completion).
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receiving 5 mg/day on this test, after week 34 (i.e.
affected not only by cognition, but also by physical 10 weeks into the open-label phase) patients receiving impairments/limitations the patient might have due to 5 mg/day donepezil had nonsignificantly better scores stroke, congestive heart failure or to having experi- on the ADAS-cog that were maintained relative to enced a heart attack. Nonetheless, once started on those of patients receiving 10 mg/day until the end of therapy, functional ADLs appeared to stabilise in the study. This pattern has been seen in a previous AD open-label, extension study, where the ‘crossover' The original two double-blind studies only enrolled occurred after about 110 weeks of uninterrupted patients with stable comorbid conditions, often several donepezil therapy (Doody et al., 2001a). The small months (at least 3) after a cardiovascular event.
number of patients in the 5 mg/day group might Patients with VaD generally stabilise until the next provide some explanation; however, the reason for this event, which possibly explains why the original studies result in the ADAS-cog remains unclear. Both doses of showed that efficacy measure scores remained close to donepezil (5 and 10 mg/day) were beneficial, and in the baseline among placebo patients (Pratt, 2002), a CDR-SB and the ADFACS tests in this study, the plateau effect also seen in other VaD clinical trial 10 mg/day donepezil dose tended to be the more populations (Kittner et al., 2000). Over time, however, beneficial dose, suggesting that the discrepant results as individual patients experience additional vascular for the ADAS-cog may be attributable to the variability events, accompanied by clinical deterioration—either of the test.
stepwise or, more commonly, gradually—this would By week 42, the mean MMSE score for all patients begin to appear as a progressive group decline. Thus, a was one point higher than at baseline. This is in positive outcome for this study would include not only contrast to the decline expected over this period with a positive result for the treatment group on one or no treatment. As change in the MMSE score can be several of the assessment measures, but also stability or directly correlated with clinical measures of function, less than expected decline.
such as dressing and toileting activities (Galasko et al., Donepezil was generally well tolerated in this study, 1995), this sustained improvement in the MMSE may in spite of patients having multiple comorbidities and represent retention of function, which is important for concomitant drug use. Moreover, tolerability data both patient quality of life (Andersen et al., 2004; from the 24-week trials were similar to the year-long Wlodarczyk et al., 2004) and for caregivers. Unlike the data, and the extension phase to 90 weeks, albeit with ADAS-cog results, MMSE scores attained by patients in fewer patients. This mirrors what has been observed in the delayed-start group at 42 and 54 weeks were clinical studies of AD patients, a population in which comparable with those of patients who had received safety data are available for up to 4.9 years (Doody donepezil from study start. The ADAS-cog results, et al., 2001b). It is, therefore, not unreasonable to however, indicated that there was still a difference in assume that donepezil can be tolerated over the long the level of cognitive function between those patients term in patients with VaD.
taking donepezil from study start and those with a There are limitations to the present study. The open- delay to initiation of active treatment. This may label design of this extension phase does not allow indicate that the ADAS-cog, which was designed comparison of treated with untreated patients in the specifically to test cognitive deficits associated with AD, longer term. Although not ideal, open-label extension is a less sensitive instrument in patients with VaD than studies do provide important information and are the MMSE, which is a general test of cognition.
necessary due to the ethical implications of performing Results with the CDR-SB were similar to those seen long-term, placebo-controlled studies in patients with with ADAS-cog: that is, improvements gained by the 5 dementia. Another possible limitation of the study is and 10 mg/day donepezil groups during double-blind related to the donepezil dosing schedules. During the treatment were mostly maintained above baseline double-blind phase, donepezil-treated patients were during the open-label phase, but patients who had been randomised to receive either the 5 or 10 mg/day dose.
delayed in receiving donepezil generally did not On enrolment in the open-label phase, all patients improve upon initiation of donepezil treatment. The received the 5 mg/day dose for 6 weeks, with some effects of treatment on function (ADFACS) were subsequently remaining on this dose, some increasing mixed. Over the course of the study, the patients' to the 10 mg/day dose temporarily, and most increas- ability to carry out ADLs, as measured by this test, ing to the 10 mg/day dose permanently. Although, it is generally deteriorated, despite continued donepezil important to consider the possible implications of treatment. The evaluation of the ability to perform these different dosage regimens when interpreting the ADLs in patients with VaD is complicated and can be current results, outcomes from the double-blind phase Copyright # 2009 John Wiley & Sons, Ltd.
Int J Geriatr Psychiatry 2010; 25: 305–313.
Long-term use of donepezil for vascular dementia  Donepezil was well tolerated over 6 months in This study was sponsored by Eisai Inc. and Pfizer Inc.
patients with VaD; 14.4% discontinued due to Study design, data collection and interpretation of the AEs, with diarrhoea being the most common results were conceived by the authors. Editorial (incidence of 8.8%).
assistance was provided by R. Daniel, PhD, at PPSI  Patients treated with donepezil for 54 continuous and was funded by Eisai Inc. and Pfizer Inc.
weeks (double-blind study plus extension study)had ADAS-cog scores at endpoint that werehigher than at baseline, including those who wererandomised to donepezil 5 mg/day in the double- blind trial.
 Patients who initiated donepezil during the open- Andersen CK, Wittrup-Jensen KU, Lolk A, Andersen K, Kragh-Sorensen P.
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