Rivastigmine in subcortical vascular dementia

Journal of the Neurological Sciences 203 – 204 (2002) 141 – 146 www.elsevier.com/locate/jns

Rivastigmine in subcortical vascular dementia: An open 22-month study Rita Moretti a,b,*, Paola Torre b, Rodolfo M. Antonello b, Giuseppe Cazzato b, Antonio Bava a b

a Dipartimento di Fisiologia e Patologia, Universita` degli Studi di Trieste, Trieste, Italy Dipartimento di Medicina Clinica e Neurologia, Ambulatorio Disturbi Cognitivi, Universita` degli Studi di Trieste, Trieste, Italy

Abstract Further to recent data indicating that patients with vascular dementia (VaD) show a cholinergic deficit, we aimed to determine whether rivastigmine, a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), has any effects on the symptoms of VaD. Patients aged 65 – 80, with a diagnosis of dementia and probable VaD, received rivastigmine 3 – 6 mg/day (n=8) or cardioaspirin (n=8) in an open study for 22 months. At 22 months, patients treated with rivastigmine showed significant improvements in executive function and behavioural symptoms (both p<0.05 vs. both baseline and control group), which were reflected in reduced caregiver stress ( p<0.05 vs. baseline and controls). Baseline scores of global response, cognition, word fluency and activities of daily living were maintained in patients receiving rivastigmine, and there was no increase in benzodiazepine or neuroleptic intake. In contrast, the control group showed no improvements in any domain, and significant deterioration in global response and executive function (both p<0.05 vs. baseline and rivastigmine group). Side effects in both groups were tolerable and there were no study withdrawals. Long-term rivastigmine treatment appeared to be safe and effective in this patient population. In particular, improvements in domains particularly relevant to this condition were observed. These benefits may reflect the drug’s dual inhibitory effects on the cholinergic system, and its particular activity in frontal areas of the brain. A large, double-blind study of rivastigmine in patients with VaD would be worthwhile. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Behaviour; Cholinesterase inhibition; Executive function; Rivastigmine; Vascular dementia

1. Introduction As the world’s population ages, the prevalence of agerelated dementias is increasing. Overall, in the Western world, vascular disease is the second most common cause of dementia, while the most common cause is Alzheimer’s disease (AD) [1]. In Europe, the prevalence of vascular dementia (VaD) is estimated to be 1.5 – 4.8% for individuals between the ages of 70 and 80 years [2]. However, in the very elderly, aged 85 years and older, the prevalence of VaD is reported to be slightly higher than that of AD (46.9% and 43.5%, respectively, with some patients possibly having mixed forms of dementia) [3]. Vascular dementia is associated with a large amount of heterogeneity, although it is possible to distinguish subtypes based on brain pathology and clinical symptoms. Apart * Corresponding author. Instituto di Clinica Neurologica dell’Universita` degli Studi di Trieste, Ospedale di Cattinara, 34149 Trieste, Italy. Tel.: +39-40-3994321; fax: +39-40-910861. E-mail address: [email protected] (R. Moretti).

from strategic infarct dementia, intracranial haematomas or mixed forms, VaD is often associated with subcortical ischaemic vascular lesions caused by small-vessel disease. The International Classification of Diseases 10th revision (ICD-10) criteria only recently identified subcortical VaD as a major subtype [4]. Two pathophysiological mechanisms may lead to subcortical VaD [5– 7]. The first involves the occlusion of an arterial lumen, and subsequently a complete lacunar infarct, and leads to dementia due to the disruption of neural pathways. The second mechanism involves critical stenosis and hypoperfusion of multiple arterioles, resulting in widespread areas of incomplete infarction of the deep white matter and consequent functional disruption of the neural network. The end stages of the two pathways are the old entities ‘lacunar state’ and ‘Binswanger syndrome’—in practice, these usually converge. Subcortical VaD is characterized by the impairment of executive functioning, goal formation, initiation, planning, organizing, self-maintenance, sequencing and abstracting [8,9]. Memory impairment is also apparent, and patients often experience depression, personality changes and emo-

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tional lability. These symptoms reflect deterioration of the frontal lobe [10]. The pathological changes associated with VaD appear to be related to cholinergic deficits. A rat model of VaD has shown significantly reduced acetylcholine (ACh) and choline levels in the cortex, hippocampus and cerebrospinal fluid [11– 13], which are correlated with impaired learning and memory [13,14]. The cholinesterase inhibitor epistigmine has been shown to improve blood flow in the rat with tandem occlusion of left middle cerebral and common carotid arteries. Epistigmine also enhanced the ischaemiainduced rostral shift of cerebral blood flow maximum in the contralateral hemisphere and the redistribution of cerebral blood flow, a phenomenon possibly related to recovery of function [15]. In humans, postmortem studies have shown that choline acetyltransferase (ChAT) activity is reduced in VaD patients, compared with controls [16,17]. Furthermore, patients with subcortical VaD have significantly lower concentrations of ACh in the cerebrospinal fluid, and these decreases are strongly correlated with cognitive deficits [18]. Cholinesterase inhibitors target the enzymes responsible for degrading ACh in the brain, and have demonstrated significant benefits in patients with AD [19,20]. Three cholinesterase inhibitors are commonly prescribed—donepezil, rivastigmine and galantamine. Donepezil and galantamine target acetylcholinesterase (AChE), while rivastigmine acts as a dual inhibitor of AChE and butyrylcholinesterase (BuChE) [21]. Both enzymes are believed to co-regulate ACh [22]. Rivastigmine has demonstrated broad, sustained benefits in patients with AD, with or without cerebrovascular risk factors, in large, randomized clinical trials [23 – 26]. We decided to study rivastigmine in a well-defined group of patients with VaD. We recently reported preliminary results, demonstrating a general stable performance in cognitive tasks and improvements in executive function and behavioural response, in a group of subcortical VaD patients treated with rivastigmine for 12 months [27]. Here, we present the complete results of the study, having completed a follow-up of 22 months for all of the patients enrolled.

2. Methods 2.1. Patients Study subjects were men and women aged 65 – 80 years with Mini-Mental State Examination (MMSE) scores of at least 12 and satisfying the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) for dementia. Study subjects also satisfied the criteria for probable VaD in accordance with the National Institute of Neurological Disorders and Stroke and the Association Internationale pour la Recherche et l’Enseignement en Neurosciences (NINDS-AIREN) [28]. A patient was diag-

nosed as having subcortical VaD when the CT scan showed moderate to severe ischaemic white matter changes [29] and at least one lacunar infarct. Brain CT scans were randomized and reassessed independently by two neurologists. In the case of disagreement, the scans were reassessed together with an experienced neuroradiologist who took the final decision. Patients were excluded if they showed signs of nonlacunar territorial infarcts or radiological signs of normal pressure hydrocephalus. Patients with previous psychiatric illness, central nervous system disorders or alcoholism were also excluded. 2.2. Study design All patients underwent a standardized baseline assessment that included a detailed history, a physical examination, laboratory tests and psychiatric evaluations. Patients were divided into two groups, manually matched for age and education levels. Group A received rivastigmine 3– 6 mg/day while Group B received cardioaspirin 100 mg/day. Patients receiving rivastigmine began treatment on the lower dose of 3 mg/day, and were titrated to the higher dose of 6 mg/day after 4 weeks. Patients in both groups were allowed to continue any previous treatments except anticholinergic therapy. All patients were followed for 22 months, with periodical neurological and neuropsychological examinations. Visits were scheduled to take place 1, 3, 8, 12, 16 and 22 months after the start of the treatment. The trial was conducted in accordance with the Declaration of Helsinki and with the Ethics Guidelines of the Institute. Written informed consent was obtained from all participants or their responsible caregivers prior to the study. Treatment compliance was monitored by the caregivers, who controlled the intake of drugs and reported any problems. 2.3. Outcome measures Global cognitive function was assessed using the MMSE [30] at each visit. In addition, since the MMSE is not sensitive to executive functions or mental slowing [31], and because dysexecutive syndrome is the core feature of VaD [8,9], executive function was assessed using the Ten-Point Clock Drawing test (TPC) [32] at each visit. Word fluency was also assessed using semantic and phonological (WFs and WFp) tests [33] at baseline, 12 months and 22 months in order to detect mild vascular cognitive impairment. At baseline, 12 months and 22 months, the index of Activity of Daily Living (ADL) [34] was used to test the performance of daily living activities, and the Instrumental Activity of Daily Living (IADL) [35] was used to assess in particular instrumental (as opposed to basic) activities. The evaluation of basic and higher functional abilities was intended to make these assessments more robust. In addition, global performance was assessed using the Clinical Dementia Rating [36] at every visit.

R. Moretti et al. / Journal of the Neurological Sciences 203 – 204 (2002) 141–146

Behavioural symptoms were assessed using the NeuroPsychiatric Inventory (NPI) [37] at every visit. In addition, new prescriptions of neuroleptics and/or benzodiazepines were recorded and compared (indicated by a binomial scale where 1=intake and 0=no intake). Caregiver’s stress was evaluated at each visit by the Relative Stress Scale (RSS) [38]. 2.4. Tolerability The incidence of potential side effects was recorded throughout the study. In particular, patients were monitored carefully for cardiac complications. Blood pressure was measured at each visit and caregivers were instructed to monitor blood pressure and heart rates of the patients. 2.5. Statistical analyses Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS, version 10.0). For each efficacy variable, changes from baseline to 22 months between Groups A and B were compared using the twosample Wilcoxon test. Results are presented as means with standard deviations, and p-values are presented where appropriate. Spearman’s rank correlation analyses were performed between global cognitive function or caregiver stress and other outcome measures.

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Table 2 Changes in outcome scores at 22 months compared with baseline in the two treatment groups (meanFS.D.) Outcome measure

Change vs. baseline at month 22 Group A

Group B

Rivastigmine (3 – 6 mg/day)

Cardioaspirin (100 mg/day)

Cognition MMSE TPC WFp WFs

1.6F4.3 2.1F1.1***,bb 1.5F14.8 4.8F6.9

0.4F1.9 0.9F0.6b 1.5F3.2 1.5F4.8

Daily function IADL ADL

0.5F1.7 0.1F0.6

0.9F2.3 0.8F1.0

Global response CDR

0.1F0.2*

0.6F0.4b

3.3F2.6**,b 0.1F0.6

0.9F1.0 0.5F0.5

8.5F5.4**,b

3.3F3.9

Behavior and social function NPI Neuroleptic or benzodiazepine uptake Caregiver stress RSS

* p<0.05 improvement over Group B. ** p<0.01 improvement over Group B. *** p<0.001 improvement over Group B. b p<0.05 change compared with baseline. bb p<0.01 change compared with baseline.

3. Results 3.1. Patients Sixteen patients, ten men and six women, were included in the study. Eight patients received rivastigmine (Group A) and eight received cardioaspirin (Group B) (Table 1). Three patients in each group (37.5%) were receiving ACE inhibitors (mean dose 33.5F5.7 mg/day) for the treatment of hypertension. Three other patients in each group (37.5%) showed signs of diabetes mellitus type 2 and were receiving medication (mainly glibenclamine 5 mg bid) for their condition; two of these patients also showed elevated blood pressure levels and were given ACE inhibitors. Two further patients in each group (25%) showed signs of hypertension

Table 1 Baseline characteristics of patients in the two treatment groups

Age in years (meanFS.D.) Gender (male/female) Education level in years (meanFS.D.) Handedness

Group A

Group B

Rivastigmine (3 – 6 mg/day)

Cardioaspirin (100 mg/day)

72.23F3.46 5:3 7.21F1.3

72.45F1.21 5:3 7.09F2.1

Right

Right

associated with valvular failure, although neither had ever experienced congestive heart failure. These patients received calcium antagonists as antihypertensive therapy (amlodipine 6F4.1 mg/day) and diuretics (amiloride and/ or hydroclortiazide, 14.7F7.5 mg/day). In addition, two more patients in each group (25%) were suffering from left ventricular hypertrophy. Focal and neurological signs such as dysarthria, weakness, slowness or spasticity were common. Brain CT scans were available for all patients, and accuracy and inter-rater reliability for the two neurologists assessing the scans were high (94.3%). All patients completed the 22-month study. 3.2. Efficacy of rivastigmine in patients with VaD The 12-month results of this study have been published previously [27]. At baseline, there were no statistical differences between the two groups on any of the scales, indicating that the patients in each group were matched for baseline symptoms of dementia. Table 2 shows the mean change in cognitive and functional rating scales in active drug and control patients at 22 months. Group A showed significant improvements in TPC scores, of 2.1 points over baseline ( p<0.01) and 3.0 points over Group B ( p<0.001) (Fig. 1). NPI scores were also significantly improved, by 3.3 points over baseline ( p<0.05)

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R. Moretti et al. / Journal of the Neurological Sciences 203 – 204 (2002) 141–146

Fig. 1. Changes in executive function, as assessed using the TPC test, in patients with subcortical VaD receiving rivastigmine (Group A, n=8) or cardioaspirin (Group B, n=8) for 22 months.

and 4.2 points over Group B ( p<0.01) (Fig. 2). CDR scores were also better in Group A than in Group B ( p<0.05). These improvements and their clinical relevance were reflected in reduced caregiver stress, as shown by an 8.5point reduction on the RSS compared with baseline ( p<0.05) and a mean treatment effect of 11.8 points ( p<0.01) (Fig. 3). Baseline scores of global performance, cognition, word fluency and daily function were maintained in Group A, and there was no increase in benzodiazepine or neuroleptic intake. Patients in Group B showed no improvements on any outcome measure, and significant deteriorations CDR (0.6 points compared with baseline; p<0.05) and TPC scores (0.9 points; p<0.05). Final scores on both of these outcome measures, and on the NPI and RSS, were significantly worse than in Group A (Table 2).

Fig. 3. Changes in caregiver stress, as assessed using the RSS, in patients with subcortical VaD receiving rivastigmine (Group A, n=8) or cardioaspirin (Group B, n=8) for 22 months.

MMSE scores correlated with RSS scores at baseline and 22 months in both groups ( p<0.05) (Tables 3 and 4). Correlations between MMSE scores and both IADL and NPI scores were observed at 22 months in Group B (both p<0.05). There was a significant correlation between RSS and NPI scores at 22 months ( p<0.05). RSS scores and benzodiazepine/neuroleptic intake were significantly correlated in both groups at baseline and in Group B at 22 months (all p<0.05). 3.3. Tolerability of rivastigmine in patients with VaD In Group A, five patients (62.5%) reported transitory nausea during the first 3 weeks (the titration phase). This resolved spontaneously upon reaching the target dose of rivastigmine 6 mg/day in three patients, and the other two patients reported modest nausea for one more week. Muscle contractions were reported in two patients (25%) during the titration phase but resolved spontaneously upon reaching the target dose on both cases. One case each (12.5%) of anorexia, syncope and postural hypotension were also reported during the titration phase. The patient developing Table 3 Correlations between global cognitive function and other outcome measures in the study Baseline

MMSE MMSE MMSE MMSE MMSE MMSE Fig. 2. Changes in behaviour, as assessed using the NPI, in patients with subcortical VaD receiving rivastigmine (Group A, n=8) or cardioaspirin (Group B, n=8) for 22 months.

vs. vs. vs. vs. vs. vs.

RSS IADL ADL CDR NPI BDZ/N

22 months

Group A

Group B

Group A

Group B

R= 0.59* ns ns ns ns ns

R= 0.69* ns ns ns ns ns

R= 0.65* ns ns ns ns ns

R= 0.78** R=0.57* ns ns R= 0.51* ns

ns=no significant correlation. Group A: rivastigmine 3 – 6 mg/day; Group B: cardioaspirin 100 mg/day. * p<0.05. ** p<0.01.

R. Moretti et al. / Journal of the Neurological Sciences 203 – 204 (2002) 141–146 Table 4 Correlations between caregiver stress and other outcome measures in the study Baseline

RSS RSS RSS RSS RSS RSS

vs. vs. vs. vs. vs. vs.

MMSE IADL ADL CDR NPI BDZ/N

22 months

Group A

Group B

Group A

Group B

R= 0.59* ns ns ns ns R= 0.54*

R= 0.69* ns ns ns ns R= 0.54*

R= 0.65* ns ns ns ns ns

R= 0.78** ns ns ns R= 0.51* R= 0.52*

ns=no significant correlation. Group A: rivastigmine 3 – 6 mg/day; Group B: cardioaspirin 100 mg/day. * p<0.05. ** p<0.01.

syncope was being treated with a neuroleptic (olanzapine 2.5 mg/day) before entering the study, and it was considered possible that the syncope was related to this treatment. Therefore, neuroleptic therapy was withdrawn and the patient’s condition improved. In Group B, three patients (37.5%) reported nausea during the titration phase. Two patients (25%) each reported anorexia and heartburn throughout the study. Constipation (two patients, 25%) and dizziness (one patient, 12.5%) were also reported. All patients completed the 22-month study. No serious adverse events, or specific or organic cardiac problems were reported. Although patients were allowed to continue any previous medication, no drug – drug interactions were reported.

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these brain areas [39]. Since the frontal lobe in particular is known to be associated with executive function and behavioural changes, the brain region selectivity of rivastigmine may also explain its efficacy in patients with subcortical VaD, since it will have been acting upon particularly relevant areas of patients’ brains. Most previous clinical trials performed in patients with VaD have achieved unsatisfactory results [40], including a trial of the AChE-selective inhibitor galantamine, which showed efficacy in patients with AD with cerebrovascular disease, but not VaD [41], suggesting that the drug’s efficacy in the former subgroup may have stemmed only from its effects on the Alzheimer’s aspect of the condition. In contrast, rivastigmine has shown efficacy in both AD with vascular disease [26] and in subcortical VaD, indicating that it affects the cholinergic deficits underlying both conditions. The results obtained from the current study may be considered limited due to the small number patients enrolled. However, the population was sufficient to provide statistically significant differences between the two groups of patients, and may be viewed as a good basis for further research in this area. In conclusion, this preliminary study in patients with subcortical VaD indicates that rivastigmine provides significant, sustained efficacy in terms of cognition, daily function and behaviour, with associated reductions in caregiver stress. A randomized, double-blind, adequately powered study of rivastigmine would be worthwhile. Future studies may help to provide a safe and efficacious treatment option for a group of patients for whom, until now, there have been few therapeutic options.

4. Discussion To our knowledge, this is the first attempt to evaluate the effects of rivastigmine in patients with subcortical VaD. Our results indicate that long-term rivastigmine treatment is effective and safe in this patient population. Long-term treatment with rivastigmine resulted in a general stability of cognitive performance and daily function, and improvements in executive function, planning behaviour, neuropsychiatric symptoms and social conduct. Moreover, a concomitant improvement in caregiver stress scores was observed. The significant correlation between these outcomes complements the fact that neuropsychiatric symptoms account for a significant amount of the distress experienced by patients and caregivers and are a major contributing factor in decisions to institutionalize patients. Rivastigmine has a dual selectivity for AChE and BuChE [21]. Since both enzymes are involved in the breakdown of ACh [22], rivastigmine may offer optimal pharmacological efficacy resulting in significant clinical benefits. In addition, rivastigmine appears to show brain region selectivity, with an affinity for frontal areas due to a preferential affinity for the G1 isoform of AChE [21]. Rivastigmine-treated patients with AD have shown significantly improved blood flow in

Acknowledgements We would like to express our thanks to Shoona Vincent, PhD, Christopher Andrews, MSc, PhD and to Sarah Clow, PhD for their precious help and suggestions during the preparation of the manuscript.

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