Original Research Article

Accepted: May 3, 2004

Dement Geriatr Cogn Disord 2005;19:51–56
Published online: September 21, 2004
DOI: 10.1159/000080972

A 12-Month Study of the Efficacy of

Rivastigmine in Patients with Advanced
Moderate Alzheimer’s Disease
Yahya Karaman a Füsun Erdoğan a Emel Köseoğlu a Tayfun Turan b
Ali Özdemir Ersoy a

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Departments of a Neurology and b Psychiatry, Medical Faculty, Erciyes University, Kayseri, Turkey

Key Words or in rivastigmine-treated patients compared with place-

Advanced moderate Alzheimer’s disease W Rivastigmine bo-treated patients. Patients benefited from high-dose
rivastigmine treatment on all outcome measures, includ-
ing the Mini-Mental State Examination, Progressive De-
Abstract terioration Scale, as well as the Global Deterioration
The efficacy of a centrally active cholinesterase inhibitor, Scale. Patients receiving rivastigmine for 12 months sig-
rivastigmine tartrate (ENA 713), in patients with ad- nificantly improved compared with placebo-treated pa-
vanced moderate Alzheimer’s disease (AD) was evaluat- tients (p ! 0.001). By 52 weeks, patients originally treated
ed in a 12-month placebo-controlled study. We aimed to with 6–12 mg/day rivastigmine had a significantly better
investigate whether there was any evidence for the ben- cognitive function than patients originally treated with
efits of rivastigmine in patients with severe disease. placebo. Long-term rivastigmine treatment appeared to
These patients were compared with matched controls. In be well tolerated in patients with advanced moderate AD
this study, 24 patients with advanced moderate AD and significantly benefits the cognitive and functional
received rivastigmine for 12 months. Another 20 patients symptoms of AD.
received placebo. Mean daily doses of rivastigmine in Copyright © 2005 S. Karger AG, Basel

the higher-dose group at 3, 6, 9, and 12 months were

6.1 B 1.0, 8.3 B 1.2, 8.9 B 1.3, and 10.7 B 1.6 mg/day,
respectively. Cognitive abilities were assessed using the Introduction
11-item cognitive subscale of the Alzheimer Disease As-
sessment Scale (ADAS-cog). Forty-five percent of place- Alzheimer’s disease (AD) is the most common type of
bo-treated patients declined by at least 4 points on the dementia encountered in older patients. While its etiology
ADAS-cog. Conversely, only 18.3% of patients treated is still unknown, the pathological manifestations of AD
with rivastigmine declined by 4 or more points. Function- seen at autopsy are unmistakable: the characteristic amy-
al disabilities, as assessed using the Disability Assess- loid plaques and neurofibrillary tangles [1, 2]. It is also
ment for Dementia Scale, remained significantly superi- recognized that cholinergic pathways in the cerebral cor-

© 2005 S. Karger AG, Basel Füsun Erdoğan

ABC 1420–8008/05/0191–0051$22.00/0 Erciyes University, Medical Faculty
Fax + 41 61 306 12 34 Neurology Department
E-Mail karger@karger.ch Accessible online at: TR–38039 Kayseri (Turkey)
www.karger.com www.karger.com/dem Tel. +90 352 4374901, Fax +90 352 4375285, E-Mail ferdogan@erciyes.edu.tr
tex and basal forebrain are compromised in patients with tigmine may delay the progression of cognitive impair-
AD, and the cholinergic deficiency that results may con- ment in advanced moderate AD. We evaluated the effica-
tribute to the cognitive deficits observed in these patients cy of rivastigmine for a period of 12 months in patients
[3–5]. Pharmacological enhancement of the surviving with advanced moderate AD.
cholinergic system may therefore provide efficacious
symptomatic treatment of AD [6–8].
To date, the most successful pharmacological approach Methods
to the treatment of AD has been with cholinesterase This was a randomized, placebo-controlled, 12-month study un-
inhibitors (ChEIs), which are felt to increase acetylcholine dertaken at the Neurology Clinic, Erciyes University Hospital, Kay-
(ACh) levels in the central nervous system by interfer- seri, Turkey. The study included male and female subjects between
ing with the hydrolysis of ACh by acetylcholinesterase 60 and 90 years of age. Patients were included in the study if they met
each of the following criteria: having a history of cognitive decline
(AChE) and/or butyrylcholinesterase [9, 10].
that was gradual in onset and progressive over a period of at least 6
ChEIs act by inhibiting the degradation of ACh. The months; meeting criteria for Alzheimer’s type dementia as described
clinical efficacy of these drugs has been characterized by in the DSM-IV [29]; diagnosis of probable AD according to the crite-
cognitive, functional, and global improvements in pa- ria of the National Institute of Neurological and Communicative
tients with AD, and there is evidence that they may delay Disorders and Stroke and AD and Related Disorders Association
[30], and an MMSE [31] score of 14 and a score of 30 on the 11-item
the progression of dementia.

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cognitive subscale of the Alzheimer Disease Assessment Scale
Various ChEIs have been approved by the US Food (ADAS-cog) [32], specially for advanced moderate AD. In all cases,
and Drug Administration to treat AD: tacrine, donepezil, the presence of AD was supported by evidence from computed tomo-
rivastigmine, and galantamine [3, 11]. Clinical use of graphic or magnetic resonance imaging studies performed during the
tacrine has been limited by the high rate of side effects 6 months prior to entry.
All patients were either fully ambulatory or able to walk with an
and need of serial blood monitoring for hepatotoxicity
assistive device and had vision and hearing sufficient for compliance
[12]. More recently, clinical trials of donepezil [13–15], with testing procedures. Female patients were either at least 5 years
rivastigmine [16–19] and galantamine [9, 20] have dem- postmenopausal or had been surgically sterilized prior to entry.
onstrated benefits on cognitive and global measures. The Patients who had been treated for AD with a cholinomimetic
randomized controlled trials supporting these claims have agent in the preceding 60 days were also excluded. Any other antide-
mentia medication (estrogen, selegiline, nonsteroidal anti-inflamma-
involved patients with mild to moderately severe AD
tory drug) had to be discontinued before entry to the study. Any other
[Mini-Mental State Examination (MMSE) score of 5–26, drugs with anticholinergic or cholinomimetic effects were avoided.
or stages 3–6 on the Global Deterioration Scale (GDS)], The use of drugs for concomitant conditions was permitted during
but unfortunately, there is little information about the the study, with the exception of sedative-hypnotics and sedating
effects of these agents on advanced AD, especially regard- cough, which were discontinued, if possible 72 h before cognitive
testing.
ing the long-term effects.
Patients with evidence of other psychiatric or neurological disor-
Rivastigmine is a pseudo-irreversible ChEI [2, 3, 9, ders and those who had clinically significant or active gastrointesti-
21]. It inhibits both AChE and butyrylcholinesterase at nal, renal, hepatic, endocrine or cardiovascular diseases were ex-
standard dosage and has shown greater selectivity for cluded from entering trial. None of the patients had a history of alco-
brain tissue in preclinical trials, particularly for the cortex hol or drug abuse, and none were known to be hypersensitive to
ChEIs.
and hippocampus [17, 22]. There are strong theoretical
Patients had a responsible caregiver, who, together with the
reasons to believe that agents inhibiting both of these patient (or an appropriate representative) provided written informed
enzymes will have greater clinical efficacy than that of consent to participate in the study.
other AChE selective agents [18, 22–24]. Since it is not The study was conducted according to the Declaration of Helsin-
associated with hepatotoxicity or elevated liver enzyme ki and subsequent revisions, and was approved by the Ethics Com-
mittee of the Erciyes University Hospital, Kayseri, Turkey.
levels, there is no requirement for liver function monitor-
Patients were randomly assigned to receive treatment with rivas-
ing with rivastigmine therapy [23, 25, 26]. The use of tigmine or placebo. Rivastigmine and placebo were administered as
rivastigmine in other dementing disorders, such as Lewy identical tablets taken twice daily. In the rivastigmine group, patients
body dementia and vascular dementia has been studied received rivastigmine twice daily with food. The dose of rivastigmine
[19, 27, 28]. was escalated every 2 weeks in increments of 1.5 mg twice a day. The
maximum possible dose was 12 mg/day rivastigmine.
Because of the paucity of information regarding the
At the conclusion of the 8-week study visit, participants who tol-
effects of rivastigmine on advanced AD, especially on the erated the drug well and perceived benefit were invited to continue
long-term effects, we aimed to study long-term effects of rivastigmine treatment. Those continuing treatment were followed at
rivastigmine treatment and to determine whether rivas- 3-month intervals with clinical assessments, routine laboratory mon-

52 Dement Geriatr Cogn Disord 2005;19:51–56 Karaman/Erdoğan/Köseoğlu/Turan/Ersoy

itoring (standard laboratory tests, ECG), ADAS-cog, MMSE, and the Table 1. Baseline characteristics of the rivastigmine and the placebo
Clinician’s Interview-Based Impression of Change plus Caregiver group
Input (CIBIC-plus) [33].
Outcome measures for the study included the ADAS-cog, and Characteristics Placebo Rivastigmine
MMSE; functional ability was assessed using the Disability Assess- (n = 20) (n = 24)
ment for Dementia Scale (DAD) [34] and the AD Cooperative Study/
Activities of Daily Living Inventory (ADCD/ADL) [35]. On the oth- Men/women 9/11 11/13
er hand, the Progressive Deterioration Scale (PDS) [36] and GDS Age, years 73.40B0.90 74.11B0.87
[37] were assessed and the values at the beginning of the treatment AD duration, years 2.0B0.1 1.9B0.1
were compared with the result after 52 weeks. Weight, kg 69.45B0.40 67.70B0.32
Results are expressed as mean B standard deviation. Compari- Total MMSE score 13.20B0.21 11.40B0.20
sons between groups were performed by means of one-way analysis ADAS-cog score 39.30B0.57 41.65B1.41
of variance (ANOVA). The threshold for determining statistical sig- Total DAD score 51.75B1.90 53.60B2.40
nificance was p ! 0.05. If ANOVA was significant, a Scheffé post hoc ADCS/ADL score 56.30B0.90 55.20B0.85
test was applied to determine between which pairs of groups the dif- CIBIC-plus 4.42B0.08 4.40B0.07
ference was. GDS 4.90B0.2 5.1B0.3
Changes in ADAS-cog and DAD scores were compared between
the treatment groups by means of ANOVA. Possible effects of base- Values are means B SEM.
line characteristics on efficacy findings were tested using ANOVA for
ADAS-cog, CIBIC-plus, MMSE, PDS, and GDS. Rates on ADAS-

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cog (changes of baseline scores) were also calculated and compared
by means of Fisher’s exact test.
All randomized patients who received trial medication were
included in the analyses of baseline characteristics. For our post hoc Table 2. Number of patients with adverse events
analysis of advanced moderate AD patients, the primary statistical
analysis was performed on the intention to treat population, using Event Placebo Rivastigmine
observed case data, as was done in the individual trials. (n = 20) (n = 24)

Nausea 15.0 16.6

Vomiting 10.0 12.5
Results Dizziness 15.0 8.3
Anorexia 10.0 8.3
Headache 0 8.3*
In this study, 24 patients with moderate advanced AD
Abdominal pain 5.0 4.1
received rivastigmine for 12 months, while another 20
patients received placebo for the same period. Patient * p ! 0.05 vs. placebo.
demographic characteristics did not differ between treat-
ment groups. The baseline characteristics of these two
groups are shown in table 1.
To establish whether the small differences between
rivastigmine and placebo baseline scores in MMSE and Treatment with high-dose (6–12 mg/day) rivastigmine
ADAS-cog have any effect on the outcome results, base- was not associated with any increase in risk for mortality,
line scores were included as a covariate in an ANOVA of significant adverse events, effects on laboratory parame-
efficacy; all ANOVA tests confirmed no significant effects ters, ECG, or cardiovascular vital signs. No consistent or
on cognitive outcomes (p 1 0.1). clinically significant drug-related laboratory abnormali-
The mean doses of rivastigmine at 3, 6, 9, and 12 ties were found with regard to vital signs, ECGs, or labo-
months were 6.1 B 1.0, 8.3 B 1.2, 8.9 B 1.3, and 10.7 B ratory values including hepatic enzymes.
1.6 mg/day, respectively. Twenty-one patients tolerated The results of the observed case analysis for primary
the drug well and reached a dose of 6–12 mg/day at 12 outcome measures at 52 weeks are provided in table 3.
months. Three patients were not able to tolerate the escal- On the ADAS-cog, patients receiving placebo steadily
ating doses of rivastigmine to optimal levels owing to the deteriorated with a mean change from baseline of 4.5
incidence of gastrointestinal side effects. These patients points. The scores of patients in the rivastigmine group
were maintained on a lower dose of rivastigmine (3–6 mg/ improved compared with their baseline values. The mean
day); mean daily doses of rivastigmine in the higher-dose changes from baseline scores for patients receiving rivas-
group at 3, 6, 9, and 12 months were 6–12. mg/day. tigmine compared with placebo were statistically signifi-
Adverse events by treatment groups are shown in table 2. cant. A significantly higher percentage of treated AD

Efficacy of Rivastigmine in Patients with Dement Geriatr Cogn Disord 2005;19:51–56 53

Advanced Moderate AD
Table 3. Primary outcome measure results after 52 weeks (observed ent from those in the placebo group for global assessment
case analysis) of change, activity of daily living and disease severity (p !
0.001).
Outcome measures Placebo Rivastigmine p value
(n = 20) (n = 21)

ADAS-cog –4.45B0.8 0.82B0.71 !0.001 Discussion

CIBIC-plus 0.51B0.2 0.16B0.14 !0.001
MMSE 1.2B0.1 0.20B0.1 !0.010
The objective of this paper was to analyze the long-
PDS –5.44B0.3 –1.14B1.1 !0.001
ADCD/ADL –0.15B0.1 –0.33B0.2 !0.012 term outcome of rivastigmine treatment and to determine
DAD –3.40B0.2 0.12B0.2 !0.001 the efficacy of rivastigmine in patients with advanced
GDS –0.34B0.1 –0.10B0.2 !0.001 moderate AD. The limitation of this trial was that the
number of the subjects included was small.
Advanced moderate AD patients were those with base-
line MMSE scores ^14 and ADAC-cog scores of approxi-
mately 6130 points [38]. This 52-week trial confirms that
patients demonstrated a clinically meaningful improve- rivastigmine is efficacious in the treatment of advanced
ment on the ADAS-cog scores as defined by a 4-point or moderate AD. Patients treated with rivastigmine demon-

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greater change from baseline. More patients receiving strated improvements in cognitive functions and in the
rivastigmine treatment as compared with those receiving global clinical function compared to placebo. There is evi-
placebo showed a clinically meaningful improvement. dence of a dose-response effect, with the patients treated
Forty-five percent of placebo-treated patients declined by with rivastigmine 6–12 mg/day showing greater improve-
at least 4 points on the ADAS-cog. Conversely, only ment than the patients treated with rivastigmine 3–6 mg/
18.3% of patients treated with rivastigmine declined by 4 day. Three patients were maintained on a lower dose of
or more points. rivastigmine (3–6 mg/day) and did not show any differ-
On the CIBIC-plus test, subjects receiving placebo ence from baseline on the MMSE and ADAS-cog. Since 3
deteriorated from their baseline scores, while the rating of patients were treated with a lower dose of rivastigmine, no
patients receiving rivastigmine showed either no deterio- statistical comparison was performed on the patients
ration or significantly less deterioration than that of treated with high-dose rivastigmine.
patients receiving placebo in all evaluation points (p ! Also in various other studies [23–39], patients treated
0.001). with the lower dose and the higher dose of rivastigmine
On activities of daily living as measured by the PDS, had significantly better cognitive functions than the place-
patients receiving placebo progressively declined, with a bo group.
mean deterioration from baseline of more than 5 points at Although there was no difference between the patient
week 52. PDS scores of rivastigmine-treated subjects and control groups regarding the ADAS-cog, MMSE,
remained steadily near baseline (1.4 points). The differ- DAD, CIBIC-plus, GDS, and ADCD/ADL scores at the
ence in scores between the rivastigmine group and the pla- beginning of the study, at the end of the study, it was
cebo group was 4 points (p ! 0.001). shown that the patients treated with rivastigmine exhib-
On the GDS, patients in the high-dose rivastigmine ited meaningful differences when compared with the pla-
group showed significantly less deterioration than those in cebo group.
the placebo group at week 52 (p ! 0.001). In the literature, there are limited studies about long-
On the MMSE, the rivastigmine-treated patients term effects of rivastigmine therapy on advanced AD.
scored significantly better than those receiving placebo. The long-term efficacy of rivastigmine was evaluated in a
Patients receiving placebo deteriorated by 1.2 points from 26-week extension phase of a 26-week, placebo-controlled
baseline on the MMSE, while those receiving rivastigmine study. At week 26, placebo-treated patients who entered
improved by 0.20 points from baseline. the extension phase had a decline on the ADAS-cog of 3.8
By the end of 12 months, ADAS-cog scores and MMSE points. After 1 year, the difference between the rivastig-
scores were significantly improved with rivastigmine over mine group (6–12 mg/day) and the placebo group showed
placebo (p ! 0.001) for cognitive functions. On the an initial improvement; i.e., the difference between the
MMSE, DAD, CIBIC-plus, GDS, and ADCD/ADL, scores of the rivastigmine group and the placebo group
scores in the rivastigmine group were significantly differ- after 52 weeks was 4.2 points [18]. A subanalysis of the

54 Dement Geriatr Cogn Disord 2005;19:51–56 Karaman/Erdoğan/Köseoğlu/Turan/Ersoy

patients with moderately severe AD, at week 52, showed least one adverse event during the trial (table 2). The inci-
that patients who had initially been treated with rivastig- dence of adverse events during the dose escalation phase
mine (6–12 mg/day) had a decline from baseline in the of the study in the rivastigmine group was greater than
mean ADAS-cog score of 1 point, whereas patients origi- that of the placebo group. During the maintenance phase,
nally randomized to the placebo group had a significantly the difference between the placebo and rivastigmine
greater decline of 5.5 points [40]. groups in the frequency of adverse events was reduced.
In various studies, patients treated with high-dose The most common adverse events were nausea (16.6%),
rivastigmine exhibited a clinically meaningful improve- vomiting (12.5%), dizziness (8.3%), anorexia (8.3%),
ment compared with patients treated with placebo [24, headache (8.3%), and abdominal pain (4.1%).
25, 40–44]. We observed less side effects than reported in the liter-
There were no obvious overall trends of clinically rele- ature. In patients with AD compared with the control
vant differences between the treatment groups in vital group, the most important side effect was headache.
signs (mean systolic and diastolic blood pressure, heart We had more favorable results than the studies in the
rate, body temperature), mean body weight, physical and literature which examined the effects of rivastigmine dur-
neurologic examination, hematological or biochemical ing 52 weeks. We recommend the use of high-dose rivas-
analysis, electrocardiographic measurement, and urine tigmine for patients with advanced moderated AD. There
analysis during the study. The adverse events associated is no study about taking AchEI for more than 1 year, but

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with rivastigmine in this study were generally those ex- patients can use AchEI for a longer period if there is no
pected from cholinergic stimulation, and similar to those side effect and as long as the patient has clinical benefits
reported with other ChEIs [25, 39]. The adverse events from it.
were generally not severe and occurred most frequently We conclude that patients with AD may continue to
during the dose escalation phase and may be reduced fur- experience efficacy benefits of clinical value from main-
ther by using a slower dose escalation [23]. tained, long-term rivastigmine treatment, even in the
Rivastigmine was well tolerated, adverse events occur- more advanced phases of the disease. Rivastigmine also
ring at least 6% more often in the rivastigmine group than appears to be well-tolerated in patients with advanced
the placebo group. More than 55% of patients in both moderate AD.
treatment groups (rivastigmine and placebo) reported at

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Erratum

Collerton D, Burn D, McKeith I, O’Brien J: Systematic review and meta-analysis show

that dementia with Lewy bodies is a visual-perceptual and attentional-executive dementia.
Dement Geriatr Cogn Disord 2003;16:229–237.
In the above cited article there was an error in table 1. The 9th row should read:

Table 1. Description of task characteristics

Characteristic Task requirement Exemplars % agreement Contribution to factors, % variance accounted for
between
general verbal/ attentional visual verbal
raters
non-verbal executive perceptual memory
30 17 14 9

Executive requires the manipulation Wisconsin card sorting 92 0.17 0.85

of rules

56 Dement Geriatr Cogn Disord 2005;19:51–56 Karaman/Erdoğan/Köseoğlu/Turan/Ersoy