Wilkinson 2003

Donepezil in vascular dementia A randomized, placebo-controlled study D. Wilkinson, MBChB, MRCGP, FRCPsych; R. Doody, MD, PhD; R. Helme, MBBS, PhD, FRACP, FFPMANZCA; K. Taubman, MBBS, FRACP; J. Mintzer, MD; A. Kertesz, MD; R.D. Pratt, MD; and the Donepezil 308 Study Group*

Abstract—Objective: To evaluate the efficacy and tolerability of donepezil in patients with vascular dementia (VaD). Methods: Patients (n ⫽ 616; mean age, 75.0 years) with probable or possible VaD, according to National Institute of Neurological Disorders and Stroke–Association Internationale pour la Recherche en l’Enseignement en Neurosciences criteria, were randomized to receive donepezil 5 mg/day (n ⫽ 208), donepezil 10 mg/day (after 5 mg/day for the first 28 days) (n ⫽ 215), or placebo (n ⫽ 193) for 24 weeks. Results: Seventy-six percent of the patients enrolled had probable VaD. A total of 75.3% of the 10 mg donepezil group and 80.8% of the 5 mg group completed the study compared with 83.4% of the placebo group. Both donepezil-treated groups showed improvements in cognitive function on the Alzheimer’s Disease Assessment Scale– cognitive subscale compared with placebo, with a mean endpoint treatment difference, as measured by the change from baseline score, of approximately 2 points (donepezil 5 mg, ⫺1.65 [p ⫽ 0.003]; 10 mg, ⫺2.09 [p ⫽ 0.0002]). Greater improvements on the Clinician’s Interview-Based Impression of Change–plus version were observed with both donepezil groups than with the placebo group (overall donepezil treatment vs placebo p ⫽ 0.008); 25% of the placebo group showed improvement compared with 39% (p ⫽ 0.004) of the 5 mg group and 32% (p ⫽ 0.047) of the 10 mg group. Withdrawal rates due to adverse events were low (placebo, 8.8%; donepezil 5 mg, 10.1%; 10 mg, 16.3%). Conclusions: Donepezil-treated patients demonstrated significant improvements in cognition and global function compared with placebo-treated patients, and donepezil was well tolerated. NEUROLOGY 2003;61:479 –486

Vascular dementia (VaD)—also known as dementia associated with cerebrovascular disease—accounts for 15 to 20% of dementia cases.1-3 Dementia is an independent risk factor for mortality in patients with ischemic stroke4; however, there are currently no approved or recommended treatments for the cognitive impairment of VaD.5 Preclinical6,7 and clinical8,9 evidence indicates that a cholinergic deficit, similar to that seen in Alzheimer disease (AD),10 may be associated with VaD, suggesting that patients with VaD may benefit from treatment with cholinesterase (ChE) inhibitors. A recent study has shown some benefits of a ChE inhibitor in patients with AD plus cerebrovascular disease.11 Moreover, treatment with donepezil, an acetylcholinesterase inhibitor that significantly benefits cognition, global function, and activities of daily living (ADL) in patients with mild to moderately severe AD,12-15 improved patients with probable VaD during a 6-month, open-label, pilot study.16 We report the results of one of the first two placebo-controlled clinical trials of the efficacy and tolerability of a ChE inhibitor in a cohort of patients

with National Institute of Neurologic Disorders and Stroke–Association Internationale pour la Recherche et l’Enseignement en Neurosciences (NINDSAIREN) criteria– diagnosed17 VaD. Methods. Study design. This was a 24-week, double-blind, randomized, placebo-controlled, parallel-group study conducted at 51 sites in the United States, Europe, Canada, and Australia. Patient population. Men or nonpregnant women of any race and at least 40 years of age were considered for inclusion. A diagnosis of possible or probable VaD of more than 3 months in duration, as defined by NINDS-AIREN criteria,17 was required for enrollment. All eligible patients were also required to exhibit clinical and radiologic evidence of cerebrovascular disease. It was inherent in the diagnosis that patients would have risk factors for hypertension, diabetes (type 1 and type 2), cardiac disease, or stroke; patients with these conditions were enrolled providing the diseases had been stable or controlled by medication for at least 3 months. The diagnosis of VaD by NINDS-AIREN criteria precludes other causes of dementia, thus excluding patients with AD and other neurodegenerative disorders that may be responsible for the dementia. Patients were also excluded from study participation if they had psychiatric disorders such as schizophrenia, a MiniMental State Examination (MMSE) score18 below 10 or above 26, new stroke within the prior 28 days, myocardial infarction within the last 3 months (although patients could be reconsidered for inclusion after 3 months had elapsed), any clinically relevant or life-threatening disease, drug or alcohol abuse, or a known hyper-

*See the Appendix for a complete list of the members of the Donepezil 308 Study Group. From Memory Assessment and Research Centre (Dr. Wilkinson), Moorgreen Hospital, Southampton, UK; Alzheimer’s Disease Center (Dr. Doody), Baylor College of Medicine, Houston, TX; National Ageing Research Institute (Dr. Helme), Parkville, Victoria, Australia; Austin and Repatriation Medical Centre (Dr. Taubman), Heidelberg, Victoria, Australia; Medical University of South Carolina (Dr. Mintzer), Alzheimer’s Research and Clinical Programs, North Charleston, SC; University of Western Ontario (Dr. Kertesz), St. Joseph’s Hospital, London, Ontario, Canada; and Eisai Inc. (Dr. Pratt), Teaneck, NJ. This report presents data generated from protocol E2020-A001-308, which was sponsored by Eisai Inc. Received November 14, 2002. Accepted in final form May 7, 2003. Address correspondence and reprint requests to Dr. David Wilkinson, Memory Assessment and Research Centre, Moorgreen Hospital, Southampton SO30 3JB, UK; e-mail: [email protected] Copyright © 2003 by AAN Enterprises, Inc.

479

sensitivity to donepezil. Most concomitant medications were permitted during the study, except other cholinesterase inhibitors and anticholinergics. The caregiver and the patient (or a legal representative) provided written informed consent prior to screening for the study. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments,19 and in compliance with United States, European Union, Canadian, and Australian clinical trials regulations. Protocol. Patients were assigned to treatment groups by a computer-generated randomization protocol. Patients were administered placebo, donepezil 5 mg/day, or donepezil 10 mg/day as single daily doses each evening before bedtime. Blinding was ensured by the use of identical-appearing placebo and donepezil tablets. Patients in the donepezil 10 mg/day group received donepezil 5 mg/day for 4 weeks and then 10 mg/day until week 24. Reduction in treatment dosage was not permitted—if patients could not tolerate their assigned dose, they were required to discontinue from the study. Clinic visits occurred at screening, at baseline, and at weeks 6, 12, 18, and 24. During these visits, psychometric evaluations, physical and neurologic examinations, laboratory determinations, vital signs measurements, medication compliance checks, and adverse event (AE) monitoring took place. If CT or MRI scans had not been undertaken within the last 6 months, they were carried out at screening. Outcome measures. Primary efficacy assessments. The primary efficacy measures were the AD Assessment Scale– cognitive subscale (ADAS-cog)20 and the Clinician’s Interview-Based Impression of Change–plus version (CIBIC-plus).21 The ADAS-cog is a sensitive psychometric scale for measuring cognitive function, routinely utilized in trials conducted in patients with AD.12,13 ADAS-cog assessment was performed by a trained clinician. An independent clinician, who was blinded to the patient’s psychometric test scores and AE information, performed the CIBIC-plus. The severity of disease (Clinician’s Interview-Based Impression of Severity [CIBIS]) was assessed at baseline, and then CIBIC-plus change from baseline scores were rated at weeks 6, 12, 18, and 24. The CIBIC-plus used in this study was developed and validated for patients with AD by the AD Cooperative Study Group.22 It is derived from a semi-structured interview conducted by a clinician with the caregiver and the patient. The CIBIC-plus interview domain questions were modified to include the range of impairments considered by the investigators to be important for patients with VaD. A range of assessments validated for use in AD were utilized in this study, as assessments specific for VaD had not been developed at the time of study design. Secondary efficacy assessments. The secondary efficacy measures utilized in this study included the MMSE18 (conducted by a trained clinician) and the Sum of the Boxes of the Clinical Dementia Rating23 (CDR-SB); this score was agreed upon by consensus among members of each patient’s assessment team. The AD Functional Assessment and Change Scale (ADFACS) was used to monitor function. The ADFACS assesses instrumental and basic ADL,15 and it should therefore be applicable to patients with VaD, provided physical impairments due to stroke or other medical conditions are taken into account.24 This was done by categorizing those patients with permanent motor or sensory deficits, in whom change in certain ADL may not be observed, as “not assessable” in affected domains, and assessing only physically unaffected domains. Safety assessments. The safety and tolerability of the study medication were assessed continually from baseline to endpoint by monitoring discontinuations from the study and by comparing treatment groups with respect to rates of AE, median changes in laboratory test values, rates of clinically relevant laboratory abnormalities, changes in vital signs, electrocardiogram abnormalities, concomitant medication use, and treatment-emergent physical examination findings. Statistical analysis. Sample size was determined following a review of the results of phase III clinical trials of donepezil in AD.12,13,25 However, the sample size was increased from 450 patients after a blinded analysis of the variance in CIBIC-plus scores in the first 100 patients enrolled in the study indicated that the SD was larger than observed in the AD studies. A revised sample size of 600 patients (200 placebo, 200 donepezil 5 mg/day, 200 donepezil 10 mg/day) was considered sufficient to detect a 0.3 unit 480

NEUROLOGY 61

August (2 of 2) 2003

Figure 1. Subject disposition. *Twenty-one patients were excluded from the intent-to-treat (ITT) population, as they did not take at least one dose of study medication, and did not have a baseline, or at least one postbaseline, assessment of at least one primary efficacy variable. †Six patients died during the study (one in the placebo group, three in the donepezil 5 mg/day group, and two in the donepezil 10 mg/day group). ‡Examples of other reasons for discontinuation included medication noncompliance (1 patient), protocol violation (5 patients), nursing home placement (4 patients), patient moved (6 patients), request of caregiver (2 patients). AE ⫽ adverse events; MMSE ⫽ Mini-Mental State Examination; AD ⫽ Alzheimer disease. difference in CIBIC-plus between active treatment and placebo at the 0.05 significance level, allowing for a discontinuation rate of 20%. Patients who withdrew from the study were not replaced. Efficacy analyses were performed on the intent-to-treat (ITT) population, defined as all patients who were randomized to treatment, received at least one dose of study medication, and who provided data at baseline and at least one postbaseline efficacy assessment. Within the ITT population, analyses of both observed cases (OC) at each scheduled visit (weeks 6, 12, 18, and 24) and last observation carried forward (LOCF) at week 24 were conducted. Week 24 LOCF using the ADAS-cog and the CIBIC-plus was defined as the primary endpoint evaluation for each patient. Additional subgroup analyses were performed on patients with possible VaD and on patients with probable VaD, as classified by the investigator according to NINDS-AIREN criteria. Analysis of safety was performed on the population that included all patients who received at least one dose of study medication and who provided any postbaseline follow-up data. Demographic characteristics and efficacy measure outcomes were examined by an analysis of covariance (ANCOVA) (for continuous variables) or by Cochran-Mantel-Haenszel test (for categorical variables). The least squares (LS) mean change from baseline scores to weeks 6, 12, 18, and 24 and endpoint are presented for all variables analyzed with an ANCOVA model. All tests were two-tailed and conducted at the 0.05 significance level.

Results. Subject disposition. A total of 887 patients were screened and 616 entered the study and were randomized to receive placebo (n ⫽ 193), donepezil 5 mg/day (n ⫽ 208), or donepezil 10 mg/day (n ⫽ 215) (figure 1). Reasons for screening failure included not meeting entry criteria (e.g., 63 patients had an MMSE score ⬍10 or ⬎26), withdrawal of consent, a diagnosis of AD, and unstable medical conditions (see figure 1). Baseline characteristics: VaD population. Overall, 76% (468/616) of enrolled patients had a diagnosis of probable VaD, and 24% (148/616) had a diagnosis of possible VaD.

Table 1 Baseline characteristics

Characteristics

Placebo, n ⫽ 193

Donepezil 5 mg, n ⫽ 208

Donepezil 10 mg, n ⫽ 215

Total, n ⫽ 616

Mean age, y, ⫾ SE (range)

74.4 ⫾ 0.6 (41–89)

74.7 ⫾ 0.6 (38–95)

75.7 ⫾ 0.6 (47–90)

75.0 ⫾ 0.3 (38–95)

88 (45.6)

78 (37.5)

81 (37.7)

247 (40.1)

Probable VaD

145 (75.1)

161 (77.4)

162 (75.3)

468 (76.0)

Possible VaD

48 (24.9)

47 (22.6)

53 (24.7)

148 (24.0)

193 (100)

207 (99.5)

213 (99.1)

613 (99.5)

Women, n (%) Diagnosis, n (%)

Abnormal CT/MRI, n (%) Medical history, n (%) Cardiovascular disease

176 (91.2)

183 (88.0)

198 (92.1)

557 (90.4)

Stroke*

130 (67.4)

138 (66.3)

142 (66.0)

410 (66.6)

Cerebral infarction*

141 (73.1)

167 (80.3)

161 (74.9)

469 (76.1)

9.6 ⫾ 0.2 (1–17)

9.4 ⫾ 0.2 (1–17)

9.5 ⫾ 0.2 (1–16)

9.5 ⫾ 0.1 (1–17)

ADAS-cog

18.8 ⫾ 0.7

20.8 ⫾ 0.7†

20.6 ⫾ 0.7

MMSE

22.2 ⫾ 0.3

21.8 ⫾ 0.3

21.5 ⫾ 0.3

Hachinski score, mean ⫾ SE (range) Psychometric score, LS mean ⫾ SE

CDR-SB

5.6 ⫾ 0.2

6.0 ⫾ 0.2

6.1 ⫾ 0.2

ADFACS

15.1 ⫾ 0.7

15.7 ⫾ 0.7

16.1 ⫾ 0.7

* The presence of stroke was determined clinically, and the presence of cerebral infarction was determined radiologically. † p ⫽ 0.048 vs placebo. VaD ⫽ vascular dementia; LS ⫽ least squares; ADAS-cog ⫽ Alzheimer’s Disease Assessment Scale– cognitive; MMSE ⫽ Mini-Mental State Examination; CDR-SB ⫽ subscale/sum of the boxes of the Clinical Dementia Rating; ADFACS ⫽ Alzheimer’s Disease Functional Assessment and Change Scale.

Almost all patients (90%) had comorbid cardiovascular disease, and most had a history of cerebral infarction (determined radiologically) (76%) and stroke (determined clinically) (67%) (table 1). The majority of the population had hypertension (72%), most had a history of smoking (61%), and many had a history of hypercholesterolemia (37%). The prevalence of these conditions was similar among the treatment groups, with the exception of a history of hypertension, which was more common in the placebo group than in the active treatment groups (placebo, 79%, donepezil 5 mg, 70%, p ⫽ 0.04; and 10 mg, 67%, p ⫽ 0.01). Hachinski Ischemia Scale (HIS) scores were similar among treatment groups (see table 1), with an average total score of more than nine. The majority of patients had an abrupt onset of dementia (placebo, 72%; donepezil 5 mg, 72%; and 10 mg, 68%), and many had shown stepwise deterioration in cognition prior to the study (placebo, 55%; donepezil 5 mg, 51%; and 10 mg, 58%). The three treatment groups were similar at baseline with respect to their demographic characteristics and psychometric test scores (see table 1), with the exception of the baseline ADAS-cog score, which was lower (better) in the placebo group than in the donepezil 5 mg/day group (p ⫽ 0.048) (see table 1). However, ADAS-cog scores were similar among the treatment groups at screening (mean ⫾ SE: placebo, 21.8 ⫾ 0.8; donepezil 5 mg, 23.5 ⫾ 0.8; and 10 mg, 23.6 ⫾ 0.8). The overall study completion rate was 79.7%, and the three treatment groups showed only small differences in completion rates (placebo, 83.4%; donepezil 5 mg, 80.8%;

and 10 mg, 75.3%) (see figure 1). Approximately half (73/ 125) of all discontinuations were due to treatmentemergent AE. Additional reasons for discontinuation included the request of the patient or investigator, protocol violation, and nursing home placement (see figure 1). The overall mean compliance rate for all visits was 97.8% (placebo, 96.7%; donepezil 5 mg, 100.2%; and 10 mg, 96.3%). At least one concomitant medication was used by 614/ 616 patients (99.7%) during the study (table 2). There were no differences in concomitant medication usage among treatment groups (placebo, 99.0%; donepezil 5 mg, 100%; and 10 mg, 100%). The most common concomitant medications were antithrombotics (81.5%; aspirin was taken by 65.6%) and agents acting on the renin-angiotensin system (36.5%). Primary efficacy outcomes. ADAS-cog. Significant differences in favor of donepezil 5 and 10 mg/day, compared with placebo, were observed on the ADAS-cog at weeks 12, 18, and 24, and also at endpoint (figure 2). The LS mean ⫾ SE change from baseline score in placebotreated patients was ⫺0.58 ⫾ 0.42 at week 24 OC, and ⫺0.10 ⫾ 0.39 at endpoint. In comparison, the LS mean ⫾ SE change from baseline scores in donepezil-treated patients were ⫺2.02 ⫾ 0.36 at week 24 OC and ⫺1.75 ⫾ 0.33 at endpoint in the 5 mg group, and ⫺2.65 ⫾ 0.48 at week 24 OC and ⫺2.19 ⫾ 0.44 at endpoint in the 10 mg group. CIBIC-plus. More patients in the donepezil 5 mg and 10 mg treatment groups than in the placebo group were rated on the CIBIC-plus as showing improvement at endpoint (% of each group showing minimal, moderate, or August (2 of 2) 2003

NEUROLOGY 61

481

Table 2 Common concomitant medications taken during the study Placebo, n ⫽ 193

Medications ⱖ1 Concomitant medication Antithrombotic agents

191 (99.0)

Donepezil 5 mg, n ⫽ 208 208 (100)

Donepezil 10 mg, n ⫽ 215 215 (100)

161 (83.4)

166 (79.8)

175 (81.4)

134 (69.4)

133 (63.9)

137 (63.7)

Agents acting on renin-angiotensin system

86 (44.6)

72 (34.6)

67 (31.2)

Vitamins

68 (35.2)

75 (36.1)

78 (36.3)

Calcium channel blockers

74 (38.3)

59 (28.4)

72 (33.5)

Analgesics

62 (32.1)

71 (34.1)

67 (31.2)

Diuretics

54 (28.0)

71 (34.1)

68 (31.6)

Antibacterials for systemic use

61 (31.6)

65 (31.3)

63 (29.3)

Serum lipid reducing agents

57 (29.5)

47 (22.6)

63 (29.3)

Cardiac therapy*

46 (23.8)

42 (20.2)

48 (22.3)

Aspirin

Values are n (%). * Cardiac therapy includes glycosides (e.g., digoxin) and nitrates (e.g., glyceryl trinitrate).

marked improvement: placebo, 25%; donepezil 5 mg, 39%; and 10 mg, 32%) (figure 3). Greater improvements on the CIBIC-plus were observed with both donepezil treatment groups than with the placebo group at endpoint (overall donepezil treatment, p ⫽ 0.008; donepezil 5 mg, p ⫽ 0.004; and 10 mg, p ⫽ 0.047). Benefits over placebo were also observed in favor of both doses of donepezil at week 12 (overall donepezil treatment, p ⫽ 0.0004; 5 mg, p ⫽ 0.003; 10 mg, p ⫽ 0.001), week 18 (overall donepezil treatment, p ⫽ 0.002; 5 mg, p ⫽ 0.041; 10 mg, p ⫽ 0.001), and week 24 (overall donepezil treatment, p ⫽ 0.01; 5 mg, p ⫽ 0.006; 10 mg, p ⫽ 0.078). Secondary efficacy outcomes. MMSE. Patients treated with donepezil 5 or 10 mg/day demonstrated significantly greater improvements on the MMSE than placebotreated patients at weeks 12, 18, and 24, and at endpoint (figure 4). Placebo-treated patients showed small postbaseline improvements in MMSE score (LS mean ⫾ SE change from baseline score at week 24 OC, 0.41 ⫾ 0.25; at endpoint, 0.23 ⫾ 0.24).

Figure 2. Alzheimer Disease Assessment Scale– cognitive subscale least squares mean change from baseline score in donepezil- and placebo-treated patients. *p ⬍ 0.05, **p ⬍ 0.01, ***p ⬍ 0.001 vs placebo. ⫽ Donepezil 10 mg/d; ⫽ donepezil 5 mg/d; —»— ⫽ placebo. 482

NEUROLOGY 61

August (2 of 2) 2003

CDR-SB. At week 12, patients receiving donepezil 5 or 10 mg/day demonstrated greater improvements on the CDR-SB than placebo-treated patients. At weeks 18 and 24, and at endpoint, placebo-treated patients showed a decline from baseline levels, whereas patients receiving donepezil (5 or 10 mg/day) continued to show improvement above baseline, with greater benefits vs placebo in the 10 mg/day group (LS mean ⫾ SE change from baseline score at week 24 OC: placebo, 0.08 ⫾ 0.14; donepezil 5 mg, ⫺0.19 ⫾ 0.14, p ⫽ 0.18; and 10 mg, ⫺0.36 ⫾ 0.14, p ⫽ 0.03; LS mean ⫾ SE change from baseline score at endpoint: placebo, 0.16 ⫾ 0.13; donepezil 5 mg, ⫺0.15 ⫾ 0.12, p ⫽ 0.07; and 10 mg, ⫺0.21 ⫾ 0.12, p ⫽ 0.03). ADFACS. ADFACS scores were maintained above baseline in patients administered donepezil 10 mg/day (LS

Figure 3. Clinician’s Interview-Based Impression of Change–plus version ratings at endpoint (week 24, last observation carried forward) in donepezil- and placebotreated patients. Overall treatment p ⬍ 0.01. p ⬍ 0.01 donepezil 5 mg/day vs placebo, p ⬍ 0.05 donepezil 10 mg/ day vs placebo. Black bars ⫽ donepezil 10 mg/d (n ⫽ 202); dark gray bars ⫽ donepezil 5 mg/d (n ⫽ 202); light gray bars ⫽ placebo (n ⫽ 188).

Table 3 Adverse events (AE) occurring in ⬎5% of patients in any group

Adverse event Any AE Body as a whole

Figure 4. Mini-Mental State Examination least squares mean change from baseline score in donepezil- and placebo-treated patients. *p ⬍ 0.05, **p ⬍ 0.01, ***p ⬍ 0.001 vs placebo. ⫽ Donepezil 10 mg/d; ⫽ donepezil 5 mg/d; —»— ⫽ placebo.

Donepezil 5 mg, n ⫽ 208

Donepezil 10 mg, n ⫽ 215

167 (86.5)

188 (90.4)

197 (91.6)

93 (48.2)

116 (55.8)

99 (46.0)

Accidental injury

19 (9.8)

35 (16.8)*

27 (12.6)

Asthenia

16 (8.3)

18 (8.7)

24 (11.2)

Back pain

6 (3.1)

12 (5.8)

3 (1.4)

Headache

16 (8.3)

15 (7.2)

14 (6.5)

Infection

26 (13.5)

36 (17.3)

30 (14.0)

Pain

19 (9.8)

16 (7.7)

13 (6.0)

42 (21.8)

39 (18.8)

42 (19.5)

12 (6.2)

11 (5.3)

13 (6.0)

7 (3.6)

3 (1.4)

11 (5.1)

65 (33.7)

83 (39.9)

96 (44.7)

11 (5.7)

17 (8.2)

19 (8.8)

Cardiovascular system Hypertension Syncope Digestive system

mean ⫾ SE change from baseline score at week 24 OC, ⫺0.38 ⫾ 0.45; at endpoint, ⫺0.23 ⫾ 0.40), reaching significance compared with placebo at week 12. Patients treated with donepezil 5 mg/day showed less deterioration than placebo, although this difference was not significant (LS mean ⫾ SE change from baseline score at week 24 OC, ⫺0.35 ⫾ 0.48; at endpoint, 0.11 ⫾ 0.45). In contrast, placebo-treated patients demonstrated a progressive decline in function, as assessed by the ADFACS (LS mean ⫾ SE change from baseline score at week 24 OC, 0.27 ⫾ 0.37; at endpoint, 0.76 ⫾ 0.39). The results for the instrumental ADL subscale of the ADFACS showed similar trends (LS mean ⫾ SE change from baseline score at week 24 OC, placebo, 0.27 ⫾ 0.28; donepezil 5 mg, ⫺0.24 ⫾ 0.37; and 10 mg, ⫺0.48 ⫾ 0.34, p ⫽ 0.109; LS mean ⫾ SE change from baseline score at endpoint, placebo, 0.46 ⫾ 0.27; donepezil 5 mg, ⫺0.03 ⫾ 0.34; and 10 mg, ⫺0.34 ⫾ 0.29, p ⫽ 0.054). Subgroup analyses. Probable VaD. Differences in favor of both doses of donepezil, compared with placebo, were observed on the ADAS-cog (LS mean ⫾ SE change from baseline score at endpoint, placebo, ⫺0.30 ⫾ 0.46; donepezil 5 mg, ⫺1.69 ⫾ 0.37, p ⫽ 0.028; and 10 mg, ⫺2.37 ⫾ 0.50, p ⫽ 0.001), with additional significant differences for 5 and 10 mg/day on the CIBIC-plus and MMSE, and for 10 mg/day only on the CDR-SB at week 24. Results in the probable VaD subgroup (placebo, n ⫽ 145; donepezil 5 mg, n ⫽ 161; and 10 mg, n ⫽ 162) were therefore very similar to those reported for the whole cohort. Possible VaD. The possible VaD subgroup (placebo, n ⫽ 48; donepezil 5 mg, n ⫽ 47; and 10 mg, n ⫽ 53) showed a similar pattern of responses to those observed in the overall cohort. Benefits in both active treatment groups compared with placebo were seen on the ADAS-cog (LS mean ⫾ SE change from baseline score at endpoint, placebo, 0.37 ⫾ 0.74; donepezil 5 mg, ⫺1.13 ⫾ 0.72, p ⫽ 0.22; and 10 mg, ⫺1.03 ⫾ 0.88, p ⫽ 0.24), CIBIC-plus, MMSE, and CDR-SB. Most of these differences were not significant; however, statistical conclusions in this subgroup are not robust owing to the small sample size. Safety. The proportion of patients with AE was similar among treatment groups, with at least one treatment-

Placebo, n ⫽ 193

Anorexia Constipation Diarrhea

9 (4.7)

11 (5.3)

5 (2.3)

20 (10.4)

24 (11.5)

40 (18.6)*

Dyspepsia

12 (6.2)

10 (4.8)

8 (3.7)

Nausea

15 (7.8)

23 (11.1)

36 (16.7)†

Vomiting

16 (8.3)

10 (4.8)

11 (5.1)

86 (44.6)

96 (46.2)

107 (49.8)

Nervous system Abnormal dreams

1 (0.5)

4 (1.9)

11 (5.1)†

Agitation

10 (5.2)

11 (5.3)

12 (5.6)

CVA (stroke)

11 (5.7)

7 (3.4)

8 (3.7)

Confusion

12 (6.2)

14 (6.7)

8 (3.7)

Depression

12 (6.2)

13 (6.3)

12 (5.6)

Dizziness

21 (10.9)

16 (7.7)

17 (7.9)

Insomnia

10 (5.2)

22 (10.6)*

21 (9.8)

Other Peripheral edema

10 (5.2)

13 (6.3)

7 (3.3)

Leg cramps

1 (0.5)

11 (5.3)†

13 (6.0)†

Rhinitis

1 (0.5)

8 (3.8)*

11 (5.1)†

Skin abrasion

7 (3.6)

11 (5.3)

Skin rash

8 (4.1)

11 (5.3)

6 (2.8)

Urinary incontinence

8 (4.1)

6 (2.9)

17 (7.9)

Urinary tract infection

15 (7.8)

22 (10.6)

14 (6.5)

12 (5.6)

Values are n (%). * p ⬍ 0.05 and †p ⬍ 0.01 vs placebo group. CVA ⫽ cerebrovascular accident.

emergent AE experienced by 86.5% of the placebo group, 90.4% of the donepezil 5 mg group, and 91.6% of the 10 mg group. The AE occurring in more than 5% of either donepezil treatment group and at least twice the incidence of the placebo group were nausea, abnormal dreams, insomnia, leg cramps, and rhinitis (table 3). There were no overall differences among the treatment groups in the incidences August (2 of 2) 2003

NEUROLOGY 61

483

Table 4 Serious adverse events (SAE) occurring in ⬎0.5% of patients overall

Serious adverse event

Placebo, n ⫽ 193

Donepezil 5 mg, n ⫽ 208

Donepezil 10 mg, n ⫽ 215

Total SAE*

33 (17.1)

31 (14.9)

33 (15.3)

CVA (stroke)

9 (4.7)

7 (3.4)

5 (2.3)

Skin carcinoma

8 (4.1)

1 (0.5)

4 (1.9)

Pathologic fracture

2 (1.0)

3 (1.4)

3 (1.4)

Pneumonia

4 (2.1)

3 (1.4)

1 (0.5)

Confusion

6 (3.1)

0

1 (0.5)

Transient ischemic attack

1 (0.5)

2 (1.0)

2 (0.9)

Angina

2 (1.0)

1 (0.5)

2 (0.9)

Syncope

1 (0.5)

2 (1.0)

2 (0.9)

Convulsion

3 (1.6)

1 (0.5)

1 (0.5)

Colitis

1 (0.5)

0

3 (1.4)

Values are n (%). * Including death. CVA ⫽ cerebrovascular accident.

of agitation or other behavioral symptoms (see table 3). The incidence of cardiovascular AE was similar among all three treatment groups. Hypertension was the most common cardiovascular AE (placebo, 12 patients; donepezil 5 mg, 11 patients; and 10 mg, 13 patients), followed by syncope (placebo, 7 patients; donepezil 5 mg, 3 patients; and 10 mg, 11 patients) (see table 3). Bradycardia was reported by less than 2% of patients overall (placebo, 4 patients; donepezil 5 mg, 2 patients; and 10 mg, 6 patients). Most AE were mild to moderate in severity, and considered by the investigator to be unrelated or to be possibly related to the study drug. Six patients died during the study (one in the placebo group, three in the donepezil 5 mg group, and two in the 10 mg group), and each of these deaths was considered by the investigator to be unrelated to the study medication (three patients died of stroke, one of pneumonia, one of pneumonia/stroke, and one death occurred following hospitalization of the patient for evaluation of hypotension and atrial fibrillation, although the exact cause of death was not specified). Serious AE (SAE) were reported at a similar frequency in all treatment groups; the number of patients experiencing SAE (other than death) was 32 (16.6%) in the placebo group, 28 (13.5%) in the donepezil 5 mg group, and 31 (14.4%) in the 10 mg group. Eighty-seven percent of SAE were considered to be unrelated to the study drug; the remainder were considered to be possibly related. The most common SAE in each group was stroke (table 4); the numbers of patients experiencing stroke were not significantly different among the three groups. Most SAE (78% of placebo, 71% of donepezil 5 mg, and 74% of 10 mg) did not lead to discontinuation from the study. There were no clinically relevant mean changes from baseline in vital signs, or in any clinical chemistry, hematology, or urinalysis tests, in either active treatment group. There were no significant differences from placebo in any treatment-emergent abnormal laboratory values. 484

NEUROLOGY 61

August (2 of 2) 2003

Discussion. In this study, patients with VaD treated with donepezil 5 mg or 10 mg once daily demonstrated significant benefits over placebotreated patients on measures of cognition (ADAS-cog and MMSE) and global function (CIBIC-plus). In addition, the donepezil 10 mg/day group showed significant improvements compared with placebo on a multidimensional rating of dementia severity, the CDR-SB. Donepezil also slowed functional deterioration in these patients, as assessed on the ADFACS, although this did not reach significance compared with placebo. In order to differentiate patients with VaD from those with AD or mixed dementia and thus ensure the inclusion of only patients with VaD, enrolled patients were required to satisfy NINDS-AIREN criteria.17 Application of these criteria resulted in a study population that was classified as 76% probable VaD and 24% possible VaD. The population studied here included subjects with a strong history of cerebrovascular and cardiac disease, and a high prevalence of hypertension and hypercholesterolemia. Most of these patients had had at least one TIA or clinical stroke prior to the diagnosis of dementia. In addition, patients had a mean HIS score of 9.5 (a score over 7 is indicative of VaD),26 the majority had an abrupt onset of dementia, and many had stepwise cognitive deterioration. These characteristics are different from those of patients who participated in previous trials of donepezil in patients with AD.12-15,27 In this study, the placebo group did not show cognitive deterioration over the 24 weeks of observation. Progression of VaD may be delayed by treatment of vascular disease risk factors,28 and in the current study, patients received optimal therapy for their concomitant conditions. This treatment may therefore have played some unknown role in delaying decline in cognitive function. The relative lack of deterioration observed in placebo-treated patients with VaD in this trial is supported by the results of previous studies that also utilized NINDS-AIREN criteria to enroll patients with VaD, in which placebo-treated groups demonstrated minimal cognitive decline over a period of up to 48 weeks.29,30 Placebo-treated patients enrolled in a recent 6-month trial of patients with AD plus cerebrovascular disease (mixed dementia) and patients with probable VaD (43% of the total cohort) showed no decline in the probable VaD subgroup after 6 months, whereas the subgroup with AD plus cerebrovascular disease showed a decline comparable with AD.11 These observations indicate that patients classified as having probable VaD not only differ from those with AD but also from those with mixed dementia, a group showing a pattern of deterioration more typical of AD than VaD. The consistency of these findings confirms that the NINDS-AIREN criteria for probable VaD can select a patient population distinct from those of probable AD and mixed dementia. In contrast to their relative cognitive stability, pa-

tients with VaD may show functional decline due to repeated cerebrovascular events, particularly stroke, that affect somatic function. As with patients with AD, patients with VaD may be unlikely to regain an instrumental ADL or ADL once they have lost that activity, even if their cognition improves. Beneficial effects on function in patients with VaD may therefore be best measured as the time to additional functional loss, as with patients with AD.15 In this study, the donepezil 10 mg/day treatment group demonstrated improved ability to perform ADL compared with the placebo group, as measured by the ADFACS, although this effect was small. The magnitude of treatment effects (effect sizes) observed in this study is smaller than those observed in similar AD studies,12,13 because of the nature of disease progression in VaD. The lack of deterioration in the VaD placebo group may make it more difficult to demonstrate drug–placebo differences, because significant treatment-related differences are driven by actual improvement, and not simply by reduced rate of decline, in the drug-treated group. It is likely that the positive effects of donepezil treatment in this study are demonstrated against stability or improvement in the placebo group. This observation is supported by the distribution of CIBIC-plus scores in this study, because the majority of placebo-treated patients with VaD were rated as “no change” at endpoint. The sensitivity of the CIBIC-plus scale may therefore be reduced in this population, because the rating is based on a seven-point scale with three of these points representing decline. One perceived weakness of the study might be that the assessments used were designed for AD, as no specific assessments for VaD had yet been developed. Thus, not all aspects of cognition relevant to VaD, such as executive function,31 were directly assessed. However, the CIBIC-plus interview was modified slightly to address impairments commonly encountered with VaD. The relatively short duration of this trial, along with the likelihood of no change in placebo-treated patients, may have made it more difficult for clinicians to detect treatment benefits. However, despite these various mitigating factors, which make it more difficult to detect a treatment difference, these results show detectable treatment benefits. In our study, donepezil-treated patients with probable or possible VaD demonstrated significant improvement on the ADAS-cog and the MMSE, relative to placebo, over 24 weeks. Subanalyses revealed similar responses in both VaD groups—those with probable VaD and those with possible VaD. Indeed, significant improvements in cognition compared to placebo are observed in the probable VaD subgroup and the possible VaD subgroup of the combined cohort of patients enrolled in this and a second, similar, donepezil trial.32 It would be consistent with the findings in probable and possible VaD, and also with the known benefits in AD, to see similar improve-

ments in donepezil-treated patients with mixed dementia. The overall safety profile of donepezil in this study is consistent with the clinical experience in patients with AD,33 and demonstrates that donepezil is well tolerated, even in a relatively frail population of elderly patients with considerable comorbidities. The proportion of patients with AE and SAE was similar among the three treatment groups. The AE reported more frequently by the donepezil- compared with the placebo-treated patients were due to cholinergic stimulation and have previously been reported in patients with AD treated with donepezil and other ChE inhibitors.12,14 Most of the SAE were associated with underlying cardiac, cerebrovascular, and peripheral vascular diseases, and did not occur with increased frequency in donepezil-treated patients. Furthermore, most SAE did not lead to discontinuation from the study, possibly because the majority were considered to be unrelated to treatment. Compared with patients with stroke who do not develop dementia, patients who develop dementia following stroke (i.e., patients with VaD or mixed dementia) have a two to three times greater risk of death, and furthermore, deaths due to cerebrovascular disease (e.g., recurrent stroke) and infection (e.g., pneumonia) are observed more frequently.4 There were six deaths in this study, five caused by stroke and/or pneumonia and all considered unrelated to study drug, emphasizing the general frailty of patients with VaD. In our study, donepezil 5 and 10 mg/day improved cognition and global function compared with placebo, and 10 mg/day was associated with a greater drug– placebo difference than 5 mg/day on a measure of dementia severity. Thus, donepezil 5 mg/day was clinically effective in this population, whereas 10 mg/ day yielded additional treatment benefits. In clinical practice, the optimal dose should be established for each patient, to ensure maximal efficacy while maintaining good tolerability. Acknowledgment The authors thank PPS International Communications (Worthing, UK) for assisting in the development of this article.

Appendix The Donepezil 308 Study Group principal investigators are as follows: Jeffrey T. Apter, Princeton Biomedical Research, Princeton, NJ; Peter M. Aupperle, COPSA Institute for AD and Related Disorders, UMDNJ/UBHC, Piscataway, NJ; Nancy R. Barbas, University of Michigan Medical Center, Ann Arbor, MI; Barry Baumel, Baumel Eisner Neuromedical Institute, Ft. Lauderdale, FL; Patricia Blanchette, Honolulu, HI; Sharon Cohen, North York Senior’s Health Center, North York, Ontario, Canada; Helen Creasey, Tony Broe, Center for Education and Research on Aging, Concord Repatriation General Hospital, Concord, NSW, Australia; Denis Crimmins, Central Coast Neuroscience Research, East Gosford, NSW, Australia; James Dexter, University of Missouri, Columbia, MO; Rachelle S. Doody, Baylor College of Medicine, Houston, TX; Eugene DuBoff, Denver Center for Medical Research, Denver, CO; Keith R. Edwards, Geriatric Neurology and Alzheimer’s Center, Bennington, VT; Larry Einbinder, Neurology Center, Rockville, MD; Karl Einhaeupl, Universitaetsklinikum Charite, Berlin, Germany; Phillip M. Green, Borgess Research Institute, Kalamazoo, MI; John Grubbs, Four Rivers Clinical Research, Paducah, KY; Danilo Antonio Guzman, SCOHS, Elizabeth Bruyere Center, Ottawa, Ontario, Canada; Hisham M. Hafez, The Institute for Clinical Research, Nashua, NH; Robert Hausner, The Institute on Aging Research Center, San Francisco, CA; Roy August (2 of 2) 2003

NEUROLOGY 61

485

Jones, Research Institute for the Care of the Elderly, St. Martin’s Hospital, Bath, UK; Jeffrey Karrasch, Peninsula Specialist Center, Kippa Ring, Queensland, Australia; Andrew Kertesz, St. Joseph’s Health Center, London, Ontario, Canada; John Knesevich, Neuroscience Options, Inc., Amherst, NH; Guy Lacombe, Institut Universitaire de Geriatrie de Sherbrooke, Sherbrooke, Quebec, Canada; Peter Londborg, Seattle Clinical Research Center, Inc., Seattle, WA; Helmi Lutsep, OHSU-Oregon Stroke Center, Portland, OR; Abe Marcadis, Maria Jurado, Clinical Studies, Boynton Beach, FL; David Ira Margolin, Margolin Brain Institute, Fresno, CA; Fred Marshall, University of Rochester, Rochester, NY; Peter N. McCracken, Glenrose Rehabilitation Hospital, Edmonton, Canada; John Merory, Austin Repatriation Hospital, Heidelberg West Vic, Australia; Barnett Meyers, NY Hospital–Westchester, White Plains, NY; Jacobo Mintzer, Medical University of South Carolina, Charleston, SC; David Nyenhuis, Stroke Research Center, Rush Presbyterian St. Luke’s Medical Center, Chicago, IL; Barry Passini, Carolina Neurologic Clinic, PA, Charlotte, NC; Andrew P. Passmore, Queen’s University, Belfast, Northern Ireland; Richard Pellegrino, Central Arkansas Research, Hot Springs, AR; Merrell Reiss, Beta Research, Inc., Westmont, IL; Peter Ripley, Clinical Studies, Cape Cod, South Yarmouth, MA; Alain Robillard, Recherche Clinique de Neurologie, Hôpital Maisonneuve-Rosemont, Montreal, Quebec, Canada; Martin Rossor, The National Hospital for Neurology and Neurosurgery, London, UK; Carl H. Sadowsky, Premiere Research Institute, West Palm Beach, FL; Douglas W. Scharre, OH State University, Columbus, OH; Alan Schneider, Pharmacology Research Institute, Northridge, CA; Stuart R. Stark, The Neurology Center, Alexandria, VA; Elisabeth Steinhagen-Thiessen, Evangelisches Geriatrie-Zentrum, Berlin, Germany; Steven Targum, Clinical Studies, Philadelphia, PA; Kim Taubman, Robert Helme, National Aging Research Institute, Parkville, Victoria, Australia; Larry Tune, Wesley Woods Geriatric Hospital, Emory University, Atlanta, GA; Mahmood A. Usman, The Alzheimer Center of Pittsburgh, Pittsburgh, PA; David G. Wilkinson, Thorn Hill Research, Hants, UK.

Disclosure Drs. Wilkinson, Doody, Mintzer, and Kertesz have received consulting fees and honoraria from Eisai Inc. for educational presentations. Dr. Doody has additionally received grants from Eisai Inc., with personal compensation and grants together totaling more than $10,000/year. Dr. Pratt is a full-time employee of Eisai Inc.

References 1. Lobo A, Launer LJ, Fratiglioni L, et al. Prevalence of dementia and major subtypes in Europe: a collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group. Neurology 2000;54:S4 –S9. 2. Ebly EM, Parhad IM, Hogan DB, Fung TS. Prevalence and types of dementia in the very old: results from the Canadian Study of Health and Aging. Neurology 1994;44:1593–1600. 3. Ott A, Breteler MM, van Harskamp F, et al. Prevalence of Alzheimer’s disease and vascular dementia: association with education. The Rotterdam Study. BMJ 1995;310:970 –973. 4. Desmond DW, Moroney JT, Sano M, Stern Y. Mortality in patients with dementia after ischemic stroke. Neurology 2002;59:537–543. 5. Doody RS, Stevens JC, Beck C, et al. Practice parameter: management of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001;56:1154 –1166. 6. Togashi H, Kimura S, Matsumoto M, Yoshioka M, Minami M, Saito H. Cholinergic changes in the hippocampus of stroke-prone spontaneously hypertensive rats. Stroke 1996;27:520 –525. 7. Kimura S, Saito H, Minami M, et al. Pathogenesis of vascular dementia in stroke-prone spontaneously hypertensive rats. Toxicology 2000;153: 167–178. 8. Tohgi H, Abe T, Kimura M, Saheki M, Takahashi S. Cerebrospinal fluid acetylcholine and choline in vascular dementia of Binswanger and multiple small infarct types as compared with Alzheimer-type dementia. J Neural Transm 1996;103:1211–1220. 9. Swartz RH, Black SE. How common is vascular compromise of cholinergic white matter pathways in a memory clinic sample? J Neurol Sci 2002;203–204:281.

486

NEUROLOGY 61

August (2 of 2) 2003

10. Perry EK, Tomlinson BE, Blessed G, Bergmann K, Gibson PH, Perry RH. Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. BMJ 1978;2:1457–1459. 11. Erkinjuntti T, Kurz A, Gauthier S, Bullock R, Lilienfeld S, Damaraju CV. Efficacy of galantamine in probable vascular dementia and Alzheimer’s disease combined with cerebrovascular disease: a randomised trial. Lancet 2002;359:1283–1290. 12. Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease. Donepezil Study Group. Neurology 1998;50:136 –145. 13. Burns A, Rossor M, Hecker J, et al. The effects of donepezil in Alzheimer’s disease—results from a multinational trial. Dement Geriatr Cogn Disord 1999;10:237–244. 14. Winblad B, Engedal K, Soininen H, et al. A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD. Neurology 2001;57:489 – 495. 15. Mohs RC, Doody RS, Morris JC, et al. A 1-year, placebo-controlled, preservation of function survival study of donepezil in AD patients. Neurology 2001;57:481– 488. 16. Mendez MF, Younesi FL, Perryman KM. Use of donepezil for vascular dementia: preliminary clinical experience. J Neuropsychiatry Clin Neurosci 1999;11:268 –270. 17. Roman GC, Tatemichi TK, Erkinjuntti T, et al. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology 1993;43:250 –260. 18. Folstein MF, Folstein FE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189 –198. 19. World Medical Association Declaration of Helsinki. Recommendations guiding physicians in biomedical research involving human subjects. JAMA 1997;277:925–926. 20. Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease. Am J Psychiatry 1984;141:1356 –1364. 21. Knopman DS, Knapp MJ, Gracon SI, Davis CS. The Clinician Interview-Based Impression (CIBI). A clinician’s global rating scale in Alzheimer’s disease. Neurology 1994;44:2315–2321. 22. Schneider LS, Olin JT, Doody RS, et al. Validity and reliability of the Alzheimer’s Disease Cooperative Study—Clinical Global Impression of Change. The Alzheimer’s Disease Cooperative Study. Alzheimer Dis Assoc Disord 1997;11:S22–S32. 23. Berg L. Clinical Dementia Rating (CDR). Psychopharmacol Bull 1988; 24:637– 639. 24. Gauthier S, Ferris S. Outcome measures for probable vascular dementia and Alzheimer’s disease with cerebrovascular disease. Int J Clin Pract suppl 2001;120:29 –39. 25. Rogers SL, Doody RS, Mohs RC, Friedhoff LT. Donepezil improves cognition and global function in Alzheimer disease: a 15-week, doubleblind, placebo-controlled study. Donepezil Study Group. Arch Intern Med 1998;158:1021–1031. 26. Hachinski VC, Iliff LD, Zilhka E, et al. Cerebral blood flow in dementia. Arch Neurol 1975;32:632– 637. 27. Pratt RD. Patient populations in clinical trials of the efficacy and tolerability of donepezil in patients with vascular dementia. J Neurol Sci 2002;203–204:57– 65. 28. Sachdev PS, Brodaty H, Looi JC. Vascular dementia: diagnosis, management and possible prevention. Med J Aust 1999;170:81– 85. 29. Kittner B, De Deyn PP, Erkinjuntti T. Investigating the natural course and treatment of vascular dementia and Alzheimer’s disease. Parallel study populations in two randomized, placebo-controlled trials. Ann NY Acad Sci 2000;903:535–541. 30. Orgogozo JM, Rigaud AS, Stoffler A, Mobius HJ, Forette F. Efficacy and safety of memantine in patients with mild to moderate vascular dementia: a randomized, placebo-controlled trial (MMM 300). Stroke 2002;33: 1834 –1839. 31. Padovani A, Di Piero V, Bragoni M, Iacoboni M, Gualdi GF, Lenzi GL. Patterns of neuropsychological impairment in mild dementia: a comparison between Alzheimer’s disease and multi-infarct dementia. Acta Neurol Scand 1995;92:433– 442. 32. Perdomo C, Pratt R. A comparison of the effects of donepezil in patients with probable and possible vascular dementia: a combined analysis of two 24-week, randomized, double-blind, placebo-controlled trials. Neurology 2002;58(suppl 3):PO5.115. 33. Pratt RD, Perdomo CA, Surick IW, Ieni JR. Donepezil: tolerability and safety in Alzheimer’s disease. Int J Clin Pract 2002;56:710 –717.

Donepezil in vascular dementia: A randomized, placebo-controlled study D. Wilkinson, R. Doody, R. Helme, et al. Neurology 2003;61;479-486 DOI 10.1212/01.WNL.0000078943.50032.FC This information is current as of August 25, 2003 Updated Information & Services

including high resolution figures, can be found at: http://www.neurology.org/content/61/4/479.full.html

References

This article cites 26 articles, 11 of which you can access for free at: http://www.neurology.org/content/61/4/479.full.html##ref-list-1

Citations

This article has been cited by 17 HighWire-hosted articles: http://www.neurology.org/content/61/4/479.full.html##otherarticles

Subspecialty Collections

This article, along with others on similar topics, appears in the following collection(s): All Clinical trials http://www.neurology.org//cgi/collection/all_clinical_trials All Cognitive Disorders/Dementia http://www.neurology.org//cgi/collection/all_cognitive_disorders_deme ntia Clinical trials Randomized controlled (CONSORT agreement) http://www.neurology.org//cgi/collection/clinical_trials_randomized_c ontrolled_consort_agreement Vascular dementia http://www.neurology.org//cgi/collection/vascular_dementia

Permissions & Licensing

Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions

Reprints

Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus

Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright . All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.