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Effects of Donepezil, Galantamine andRivastigmine in 938 Italian Patients withAlzheimer’s DiseaseA Prospective, Observational Study

Aurelia Santoro,1,2 Paola Siviero,3 Nadia Minicuci,3 Elena Bellavista,1,2 Michele Mishto,1,2,4

Fabiola Olivieri,5,6 Francesca Marchegiani,7 Andrea Maria Chiamenti,8 Luisa Benussi,9

Roberta Ghidoni,9,10 Benedetta Nacmias,11 Silvia Bagnoli,11 Andrea Ginestroni,11

Osvaldo Scarpino,12 Emidio Feraco,13 Walter Gianni,14 Guido Cruciani,15 Roberto Paganelli,16

Angelo Di Iorio,16 Mario Scognamiglio,17 Luigi Maria Edoardo Grimaldi,18 Carlo Gabelli,7

Sandro Sorbi,10 Giuliano Binetti,8 Gaetano Crepaldi3 and Claudio Franceschi1,2

1 Department of Experimental Pathology, University of Bologna, Bologna, Italy

2 Interdepartmental Center for Studies on Biophysics, Bioinformatics and Biocomplexity

‘L. Galvani’ (CIG), University of Bologna, Bologna, Italy

3 National Council Research, Institute of Neuroscience, Padova, Italy

4 Institute of Biochemistry, Medical Faculty Charite, Berlin, Germany

5 Department of Molecular Pathology and Innovative Therapy, Polytechnic University of Ancona,

Ancona, Italy

6 Center of Cytology, Italian National Research Center on Ageing (INRCA), Ancona, Italy

7 Center of Genetics and Molecular Biology, Italian National Research Center on Ageing (INRCA),

Ancona, Italy

8 Research Consortium Luigi Amaducci (CRIC), Arcugnano (Vicenza), Italy

9 NeuroBioGen Lab-Memory Clinic, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS)

‘Centro S. Giovanni di Dio-FBF’, Brescia, Italy

10 Proteomics Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) ‘Centro S. Giovanni

di Dio-FBF’, Brescia, Italy

11 Department of Neurological and Psychiatric Sciences, University of Florence, Florence, Italy

12 Neurology Unit, Geriatric Hospital, Italian National Research Center on Ageing (INRCA),

Ancona, Italy

13 Italian National Research Center on Ageing (INRCA), Cosenza, Italy

14 Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Italian National Research Center on Ageing

(INRCA), Rome, Italy

15 Italian National Research Center on Ageing (INRCA), Fermo, Italy

16 Department of Medicine and Sciences of Aging, Laboratory of Clinical Epidemiology, University G.

D’Annunzio, Chieti, Italy

17 Department of Elderly Assistance, Azienda Sanitaria Locale NA 1, Naples, Italy

18 Department of Neurology, Fondazione Istituto San Raffaele ‘G. Giglio’ di Cefalu, Cefalu, Italy

Approval for publication Signed Date Number of amended pages returned

ORIGINAL RESEARCH ARTICLECNS Drugs 2010; 24 (1): 1-14

1172-7047/10/0001-0001/$49.95/0

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Abstract Background: Acetylcholinesterase inhibitors (AChEIs) have been used to

improve cognitive status and disability in patients with mild to moderate

Alzheimer’s disease (AD). However, while the efficacy of AChEIs (i.e.

how they act in randomized controlled trials) in this setting is widely

accepted, their effectiveness (i.e. how they behave in the real world) remains

controversial.

Objective: To compare the effects of three AChEIs, donepezil (Aricept�),

galantamine (Reminyl�) and rivastigmine (Exelon�), in an Italian national,

prospective, observational study representative of the ‘real world’ clinical

practice of AChEI treatment for AD.

Methods: 938 patients with mild to moderate AD collected within the frame-

work of the Italian National Cronos Project (CP), involving several UVAs

(AD Evaluation Units) spread over the entire national territory, who were

receiving donepezil, galantamine or rivastigmine were followed for 36 weeks

by measuring: (i) function, as determined by the Activities of Daily Living

(ADL) and Instrumental Activities of Daily Living (IADL) scales; (ii) cog-

nition, as measured by the Mini-Mental State Examination (MMSE) and

the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog)

[primary outcome measures]; and (iii) behaviour, as measured on the Neuro-

psychiatric Inventory (NPI) and Clinical Dementia Rating (CDR) scale.

Moreover, all patients were genotyped for apolipoprotein E (apoE) genetic

variants.

Results: No statistically significant improvement in the primary outcome

measures (MMSE and ADAS-Cog) was observed with drug therapy at

36 weeks, at which point all groups had lost, on average, 1 point on theMMSE

and gained 2–3 points on the ADAS-Cog scale compared with baseline. On

the secondary outcome measures at week 36, all treatment groups showed a

significant worsening on the ADL and IADL scales compared with baseline,

while on the NPI scale there were no significant differences from baseline

except for the galantamine-treated group which worsened significantly.

Moreover, patients receiving galantamine worsened significantly compared

with the donepezil-treated group on the IADL scale. ApoE e4 allele did not

influence the effect of drug therapy.

Conclusion: Over a 36-week follow-up period, no significant difference in the

effects of donepezil, galantamine and rivastigmine on a variety of functional

and cognitive parameters was observed in a large number of apoE-genotyped

patients with mild to moderate AD recruited within the framework of a

national project representative of the scenario usually encountered in actual

clinical practice in Italy. The limitations (possibility of administration of

lower drug doses than are used in clinical trials, relatively short follow-up

period and the lack of randomization) and strengths (large number of

patients, concomitant observation of the three drugs and the number of

parameters assessed, including apoE genotype) of the present study are ac-

knowledged. Our type of naturalistic study should complement clinical trials

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because ‘real world’ practice operates in the face of the numerous variables

(e.g. health status and co-morbidities) associated with a complex disease such

as AD in elderly people.

Background

With no disease-modifying therapy for Alzhei-mer’s disease (AD) available as yet, the targets ofdrug therapy for this disorder are temporaryimprovement, stabilization and retardation of cog-nitive decline and improvement of behaviouralsymptoms. In accordance with the ‘cholinergic hy-pothesis’ for AD, several acetylcholinesterase in-hibitors (AChEIs), such as donepezil, galantamineand rivastigmine, have been used for the treatmentof patients withAD.[1] Donepezil has been found toimprove cognition and preserve function in patientswith mild to moderate AD as well as in individualswith severe AD.[2] Rivastigmine significantly im-proved cognitive function and global performancesin patients with AD,[3] and several different methodsfor administering this drug, including transdermalpatches, have been developed.[4,5] Galantamine hasbeen shown to achieve significant benefits in cog-nition and global function in patients with AD.[6,7]

On the whole, the efficacy of AChEIs, i.e. how theyact in randomized controlled trials, in patients withmild to moderate AD is widely accepted,[8-11] al-though a recent meta-analysis drew a differentconclusion.[12] On the other hand, the effectivenessof AChEIs, i.e. how they behave in the real world,remains controversial.

Only a few studies comparing the effects ofdonepezil, galantamine and rivastigmine havebeen conducted.[13-17] These studies differ in thenumber of patients included (<300 subjects inmost of the studies), their geographical origin, thelength of follow-up and their study design (ran-domized controlled trials or naturalistic studies).To our knowledge, no clear difference has beenreported among donepezil, galantamine or rivas-tigmine treatments,[13-16] except in one study inwhich donepezil therapy was associated withsignificantly greater improvements in cognitioncompared with galantamine.[17] Comparisonsamong these studies are hampered by a variety of

factors, including differences in patient baselinecharacteristics and methods used to assess effi-cacy, effectiveness and safety. Accordingly, wethought it was worthwhile to compare the effec-tiveness of the three above-mentioned drugs in alarge cohort of patients, i.e. 938 patients with ADrecruited within the framework of the ItalianNational Cronos Project (CP) commenced by theItalian Ministry of Health in October 2000, asample which was considered representative ofthe scenario encountered in ‘real world’ clinicalpractice relating to AD in Italy.

The main objectives of this study were: (i) tocompare the effects of donepezil, galantamine andrivastigmine treatments on: (a) function (dailyactivities), using the Activities of Daily Living(ADL) and Instrumental Activities of Daily Living(IADL) scales; (b) cognition, using the Mini-Mental State Examination (MMSE) and the Alz-heimer’s Disease Assessment Scale-cognitivesubscale (ADAS-Cog), which also allowed us toclassify patients as responders and nonresponders;(c) behaviour, using the Neuropsychiatric Invent-ory (NPI) and the Clinical Dementia Rating(CDR) scale; and (ii) to determine if apolipopro-tein E (apoE) genotype influenced response toAChEIs. The presence of apoE e4 is the most im-portant known risk factor for AD, while otherapoE isoforms (apoE e2, apoE e3) appear to exerta protective effect.[18]

Patients and Methods

Patients Recruitment and CronosProject Description

Weobserved 961 subjects withmild tomoderateAD consecutively recruited from October 2000 toDecember 2001, with follow-up information re-gistered for 36 weeks. All of the patients were re-ferred to ten ADEvaluation Units (UVAs) locatedin several Italian regions: Lombardia, Veneto,

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Toscana, Marche, Abruzzo, Campania, Calabriaand Sicilia, then consecutively admitted to the CPfromMay 2001 to April 2004. For this project, 501UVAs have been established in Italy. The UVAsrepresent a key element in the service networks forthe care of patients with AD, since they are themost obvious reference point for family physiciansand caregivers. Patients can be referred to UVAsby request of family physicians or caregivers. In thepresent study, each of the participating UVAs wasconstituted by a team of physicians (see below)with long experience in the field of dementia, thusassuring a high-quality standard of care. CP was adrug utilization study conducted by the ItalianMinistry of Health to monitor patients diagnosedby skilled evaluation units as having probable ADaccording to National Institute of Neurological andCommunicative Diseases and Stroke/Alzheimer’sDisease and Related Disorders Association(NINCDS-ADRDA) criteria,[19] with the mainpurpose being to provide free AChEIs to thesepatients. Starting dose and titration were estab-lished according to the recommendations of man-ufacturers: target daily doses were 5–10mg fordonepezil (Aricept�; Pfizer Italia S.r.l. Borgo SanMichele, Latina, Italy), 3–12mg for rivastigmine(Exelon�; Novartis Farmaceutica, S.A. Barcelona,Spain) and 8–16mg for galantamine (Reminyl�;Janssen-Cilag S.p.A, Cologno Monzese, Milan,Italy). In each case, clinicians were free to choosethe type and the dose of AChEI for all patients,increasing the dose from the starting point andduring follow-up. Each patient underwent a com-prehensive geriatric assessment, including an ex-tended neuropsychological evaluation based onthe collaboration of geriatricians, neurologists,psychiatrists and trained nurses. Patients includedin CP were required to score 10–26 on theMMSE[20] at the first visit to the UVA and to haveexperienced typical AD disturbances for at least6 months. No other inclusion or exclusion criteriawere established.

Evaluation of Mental Health

The MMSE, ADAS-Cog and the NPI wereadministered at baseline, at week 12 (t12) and atweek 36 (t36). The CDR scale[21] was adminis-tered only at baseline.

The MMSE is a quick way to evaluate cogni-tive function and is often used to screen for de-mentia or monitor its progression.[20] TheMMSEtests orientation, registration, attention and cal-culation, recall, praxis and language, and isscored on a 30-point scale (30 being normal and1 being severely impaired).

The ADAS-Cog examines selected aspects ofcognitive performance including elements of mem-ory, orientation, attention, reasoning, language andpraxis.[22] The ADAS-Cog scoring range is from0 to 70, with higher scores indicating greatercognitive impairment.

The NPI[23] assesses 12 neuropsychiatric dis-turbances common in dementia: delusions, hallu-cinations, agitation, dysphoria, anxiety, apathy,irritability, euphoria, disinhibition, aberrant motorbehaviour, night-time behaviour disturbances andeating disturbances. It is scored from 1 to 144, withthe score being calculated from the product of thefrequency and severity of disturbances, each ofwhich is independently assessed.

The CDR[21] is a 5-point scale used to character-ize six domains of cognitive and functional perfor-mance applicable to AD and related dementias:memory, orientation, judgement and problem sol-ving, community affairs, home and hobbies, andpersonal care. The information required to makeeach rating is obtained by a semi-structured inter-view of the patient and a reliable informant orcollateral source (e.g. family member).

Evaluation of Physical Health

ADL and IADL scales were administered atbaseline and at follow-up visits to asses func-tional capabilities. The ADL scale is based on thelevel of dependence in performing six daily ac-tions: bathing with a sponge, bath or shower;dressing; toilet use; transferring in and out of abed or chair; urine and bowel continence; andeating. Dependence in ADLs increases as thescore approaches 6.[24] The IADL scale is basedon 7 criteria (use of the telephone, traveling viacar or public transportation, food or clothesshopping, meal preparation, housework, medi-cation use, and management of money) and each

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criteria is graded on a 3-part scale: independent,assistance needed and dependent.[25]

Evaluation of Drug Effects

The primary measure of a drug’s effect wasdetermined by the mean changes in MMSE andADAS-Cog scores from baseline to t12 and t36.The secondary measures of a drug’s effect weredetermined from the mean changes in ADL,IADL and NPI scores from baseline to t12 andt36. Analyses were conducted comparing baselinewith t12 and t36 to show the effects of the threedrugs at the mid- and end-term points of thestudy.

Responders

Two means of classifying responders based onMMSE scores were developed to enhance thereporting of results: case 1, stable: patients whoseMMSE score at t36 lay within 1 standard devia-tion (SD) from baseline; improved: patientswhose MMSE score at t36 was >1 SD from base-line; worsened: patients whose MMSE scoreat t36 was <1 SD from baseline; and case 2, stable/improved: patients whose difference in MMSEscore (t36 – baseline) was zero or greater; wor-sened: patients whose difference in MMSE score(t36 – baseline) was <0.

The classification of responders/nonrespondersbased onADAS-Cog score improvement frombase-line to t36, based on US FDA[26] and the EuropeanAgency for the Evaluation of Medical Products[27]

definitions, was as follows: (i) no change or im-provement (change from baseline zero or less);(ii) improvement of ‡4 points (change frombaseline -4 or better); and (iii) improvement of‡7 points (change from baseline -7 or better).

Apolipoprotein E (apoE) Genotyping

apoE genotyping was carried out usingpolymerase chain reaction amplification andHhal restriction enzyme digestion. The genotypewas resolved on 4% Metaphor Gel (BioSpa,Milan, Italy) and visualized by ethidium bromidestaining.[28]

Statistical Analysis

Calculation of the study power was performedwith PASS 2008 (NCCS, Kaysville, UT, USA)and was based on the assumption of detecting atleast a 1 point difference in mean changes inMMSE and IADL scores (from baseline to t12and t36) across drugs, assuming a common SDwithin a group of 2.60 for MMSE and 1.30 forIADL. A difference lower than 1 point would notbe considered clinically significant for our pur-pose. The total sample of 815 completers(patients who completed the full 36-week assess-ment) analysed had a power of 83% for MMSEand 95% for IADL to detect a difference of atleast 1.00 point using the Tukey-Kramer (pair-wise) multiple comparison test at a 0.05 sig-nificance level.

The analysis of the drug effect on primarymeasures (MMSE and ADAS-Cog) by treatmentwas performed using the general linear model(GLM) including baseline score as a covariate.Multiple mean comparisons were performed withthe Bonferroni correction.

The comparability of treatment groups forsociodemographic and health status character-istics was assessed by the chi-squared (w2) test forqualitative variables and by the GLM for con-tinuous variables; homoscedasticity was firstchecked by the Levene’s test and then the Welchprocedure if heteroscedasticity was assessed. Forall quantitative variables, within-group meancomparisons across waves were verified by thepaired t-test.

Results

Study Attrition

A total of 961 subjects participated in the pro-ject but 23 were excluded from the analysis becausethey were already receiving treatment for AD.Of the remaining 938 subjects, 57.7% (n= 541)received donepezil, 11.2% (n= 105) received galan-tamine and 31.1% (n= 292) received rivastigmine.Between baseline and t12, 22 patients changedtreatment drug andwere therefore excluded (n= 10,n = 2 and n = 10 among donepezil, galantamineand rivastigmine recipients, respectively). The

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Table I. Patient sociodemographic and health status characteristics by drug therapy (values are presented as percentages or as mean – SD)

Variable Donepezil Galantamine Rivastigmine p-Valuea

No. of patients

t0 541 105 292

t12 517 100 274

t36 491 94 234

Sex (male) 34.0 45.7 31.2 0.025

Age (y) 75.9 – 7.3 76.1 – 6.4 76.1 – 6.8 NS

Education (y) 5.7 – 3.7 6.0 – 3.7 5.3 – 3.0 NS

Alcohol consumers 34.6 54.3 32.9 0.0013

Ex- or current smokers 29.0 33.3 26.0 <0.0001

Health status (t0)

diabetes mellitus 13.9 15.2 15.4 NS

dyslipidaemia 20.9 27.6 16.4 0.041

hypertension 46.2 41.9 54.1 0.047

cranial trauma 11.6 15.2 11.3 NS

anaesthesia (for surgery) 46.8 55.2 49.3 NS

Physical and cognitive functioning (CDR, t0)

normal 0.9 0 0.3 NS

uncertain 33.1 39.0 31.5 NS

mild 44.4 31.4 42.1 NS

moderate 19.4 24.8 23.6 NS

severe 1.1 1.9 1.7 NS

missing data 1.1 2.9 0.7 NS

Onset (y)

<1 42.0 39.0 42.5

1–3 23.8 18.1 28.4

>3 14.8 13.3 11.3

missing data 19.4 29.5 17.8

Primary outcome measures

MMSE (t0) 20.00 – 4.19 19.46 – 4.03 19.63 – 4.31 NS

MMSE (t12) 20.36 – 4.69 19.45 – 4.46 20.00 – 4.63 NS

MMSE (t36) 19.50 – 4.86 18.56 – 5.06 19.07 – 5.04 NS

ADAS-Cog (t0) 26.5 – 10.76 (n = 367) 28.08 – 11.03 (n = 71) 27.74 – 10.81 (n = 220) NS

ADAS-Cog (t12) 25.66 – 11.53 (n = 287) 25.38 – 9.95 (n = 52) 26.16 – 10.78 (n = 165) NS

ADAS-Cog (t36) 28.28 – 12.59 (n = 323) 30.33 – 12.59 (n = 58) 29.45 – 12.05 (n = 160) NS

Secondary outcome measures

ADL (t0) 4.96 – 1.47 5.00 – 1.41 5.05 – 1.33 NS

ADL (t12) 4.90 – 1.47 4.95 – 1.41 5.00 – 1.28 NS

ADL (t36) 5.00 – 1.44 5.12 – 1.31 5.09 – 1.29 NS

IADL (t0) 4.19 – 2.41 3.73 – 2.40 4.19 – 2.41 NS

IADL (t12) 4.03 – 2.32 3.55 – 2.36 3.97 – 2.26 NS

IADL (t36) 3.62 – 2.25b 2.73 – 2.21b,c 3.44 – 2.27c 0.0021

NPI domain (t0)

agitation 31.6 37.1 29.5 NS

hallucinations 11.5 13.3 10.3 NS

Continued next page

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most frequent reasons for changing drug were theonset of adverse effects such as vomiting, nauseaand diarrhoea. Twenty patients were considereddropouts (3 adverse events, 1 no clinical im-provement, 2 deaths, 14 lost to follow-up) andfive patients skipped the t12 visit.

Between t12 and t36, another 27 patientschanged treatment drug and were therefore alsoexcluded from this phase of the analysis (n = 14,n= 1 and n = 12 among donepezil, galantamineand rivastigmine recipients, respectively). Rea-sons for changing drug during this period in-cluded onset of adverse events such as nausea(n = 4), agitation (n = 3) and vomiting (n= 2). Fiftypatients were considered dropouts (4 adverse events,1 no clinical improvement, 2 deaths, 43 lost to fol-low-up). No statistical difference was found be-tween the drugs and the reasons for dropping out ofthe study (p= 0.35).

Patient Characteristics and Drugs

Patient characteristics at baseline, t12 and t36are summarized in table I. About 40% of patientshad AD for <1 year and there was no statisticalassociation between onset of AD and selection of

drug therapy. At baseline, there was a significantlyhigher proportion of men (45.7%), consumers ofalcohol (54.3%), ex- or current smokers (33.3%)and dislipidaemia (27.6%) among individualstreated with galantamine, while a higher pre-valence of hypertension (54.1%) was seen amongsubjects treated with rivastigmine. However, thethree groups were similar with respect to MMSE,ADAS-Cog, ADL, IADL and NPI mean scores,although the mean IADL score at t36 was lower inthe galantamine-treated group than in the done-pezil-treated group (p= 0.0014) or in the rivas-tigmine-treated group (p= 0.0325). CDR scoreswere distributed evenly across treatments.

As noted in the previous paragraph, galanta-mine was administered to the subjects with agreater number of risk factors (higher propor-tions of alcohol consumers, ex- or current smo-kers and patients with dyslipidaemia). Suchan unbalanced distribution reflects the over-all imbalance of the CP sample, of which thegalantamine-treated group comprised only 4%.Galantamine has been marketed in Italy onlysince 2001 (after the start of the CP), whereasdonepezil and rivastigmine have been marketedfrom 1997 and 1999, respectively.

Table I. Contd

Variable Donepezil Galantamine Rivastigmine p-Valuea

anxiety 39.4 39.0 39.4 NS

apathy 45.8 41.0 47.9 NS

aberrant motor behaviour 16.6 17.1 18.2 NS

eating disturbances 14.0 21.9 17.1 NS

night-time behaviour disturbances 16.6 15.2 22.6 NS

delirium 17.2 13.3 12.3 NS

depression 44.0 41.0 47.9 NS

disinhibition 11.3 10.5 9.9 NS

euphoria 6.3 5.4 6.2 NS

irritability 33.3 31.4 30.5 NS

NPI (t0) 13.60 – 15.74 (n = 537) 12.21 – 11.57 (n = 104) 13.58 – 16.05 (n = 289) NS

NPI (t12) 12.87 – 15.30 (n = 512) 12.13 – 12.96 (n = 99) 13.00 – 15.94 (n = 272) NS

NPI (t36) 13.10 – 14.48 (n = 485) 14.09 – 13.77 (n = 93) 12.35 – 14.35 (n = 233) NS

a Chi-squared (w2) test or general linear model procedure.

b Donepezil vs galantamine; p = 0.0014.

c Rivastigmine vs galantamine; p = 0.0325.

ADAS-Cog = Alzheimer’s Disease Assessment Scale-cognitive subscale; ADL = Activities of Daily Living; CDR = Clinical Dementia Rating;

IADL = Instrumental Activities of Daily Living; MMSE = Mini-Mental State Examination; NPI = Neuropsychiatric Inventory; NS = not significant;

t0 = baseline; t12 = wk 12; t36 = wk 36.

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At baseline, most patients were treated with thelowest recommended dose in the donepezil group(98.5% 5mg/day, 1.5% 10mg/day), in the galanta-mine group (11.4% 4mg/day, 84.8% 8mg/day, 3.8%16mg/day) and in the rivastigmine group (17.1%1.5mg/day, 78.8% 3mg/day, 0.7% 4.5mg/day, 2.7%6mg/day, 0.7% 7.5mg/day). During treatment,clinicians increased doses according to the healthstatus of the patients; by 36 weeks of treatment, theinitial dose had been doubled in most patients in thedonepezil group (45.2% 5mg/day, 54.8% 10mg/day),the galantamine group (1.1% 4mg/day, 33.0%8mg/day, 4.3% 12mg/day, 53.2% 16mg/day, 8.5%24mg/day) and the rivastigmine group (21.8%3mg/day, 13.2% 4.5mg/day, 41.0% 6mg/day, 3.0%7.5mg/day, 19.7% 9mg/day, 1.3% 12mg/day).

Drug Effect

The primary overall treatment effect was eval-uated from baseline to t12 and t36 by the meanchanges inMMSE andADAS-Cog scores (figure 1);secondary outcome measures were estimated byADL, IADL and NPI mean changes (table II). Nosignificant improvements from baseline to t12 andt36 were seen in the three groups on any outcomemeasures, other than in the donepezil-treatedgroup, which improved by gaining a mean 0.34points on the MMSE from baseline to the firstfollow-up (t12) [p= 0.0046]. The rivastigmine-trea-ted group showed a mean 0.26-point gain inMMSE score from baseline at this time-point, butthis was not statistically significant. In general, att36 all groups declined by losing a mean 1 point onthe MMSE and gaining between 2 and 3 points onthe ADAS-Cog scale versus baseline. Consideringthe secondary outcome measures, at t36 all groupsworsened, losing from 0.4 to 0.5 points on theADL scale and from 0.6 to 1.0 points on the IADLscale. As for the NPI scale, there were no signifi-cant differences from baseline except for the ga-lantamine-treated group, which gained 2.6 points(p= 0.0046). There was a trend toward worseningon this scale for the rivastigmine-treated group(p= 0.0859).

The comparisons of primary and secondaryoutcome measures (mean values across treat-ments) showed no statistical differences amongtreatment groups. One exception was seen in thegalantamine-treated group, which worsened sig-nificantly by losing a mean 0.88 points on theIADL compared with the donepezil-treated group(-0.40 point; p = 0.002). This group also showeda trend toward worsening on the IADL com-pared with the rivastigmine group (-0.54 point;p = 0.0718), and toward gaining on the NPI(mean increase of 3.63 points) compared with thedonepezil-treated group (p = 0.0587).

Classification of Responders Basedon Mini-Mental State Examination (MMSE)Score Changes

Case 1

The mean (–SD) difference in MMSE scorebetween baseline and t36 (t36–t0) was -0.73 – 3.05

−1.2

−1.0

−0.8

−0.6

−0.4

−0.2

0

0.2

0.4

0.6

*

0 12 36

LS m

ean

chan

ge in

MM

SE

sco

re

0 12

Time (wk)

36−0.5

0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

LS m

ean

chan

ge in

AD

AS

-Cog

sco

re

b

a DonepezilGalantamineRivastigmine

Fig. 1. Least square (LS) mean change from baseline in (a) Mini-Mental State Examination (MMSE) score and (b) Alzheimer’s Dis-ease Assessment Scale-cognitive subscale (ADAS-Cog) score fordonepezil, galantamine and rivastigmine (standard error values arereported in table II). * Indicates a significant effect of donepezil on theMMSE at 12 weeks (p = 0.0046).

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points. Classification of responders based onthe SD criteria (see Responders section above)identified improvement in about 13.2% of pa-tients in the donepezil-treated group, 12.8% in thegalantamine group and 14.6% in the rivastigminegroup (figure 2a). No statistical association wasfound (p = 0.34) between treatment and the dis-tribution of responders and non-responders.

Case 2

The classification of ‘stable/improved’, definedas having the MMSE difference score (t36–t0) of‡0, was applicable to 44.6%, 42.5% and 44.6% ofpatients in the donepezil, galantamine and rivas-tigmine groups, respectively (figure 2b). How-ever, no statistical association was found(p = 0.93) between treatment and the distributionof responders and non-responders.

Classification of Responders Based onAlzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) ScoreChanges

The percentage of patients showing no changeor increase in ADAS-Cog score varied from

62.8% in the donepezil group to 72.4% in thegalantamine group; the highest percentages ofpatients with increases of ‡4 points or ‡7 pointswere found in the galantamine-treated group(43% and 31%, respectively) [figure 2c]. However,none of the ADAS-Cog score classifications wasfound to be statistically associated with the typeof drug administered.

Stratification by apoE4 Allele Carriage

All subjects were genotyped for the apoEgene and classified as either apoE e4 allele car-riers (41.1%) or non-carriers (57.1%); 1.8% ofpatients had missing data. The primary outcomemeasures were analysed by apoE e4 allele car-riage and non-carriage (table III). No statisticallysignificant differences were found when compar-ing drug therapy or primary outcomes for apoEe4 allele carriers with non-carriers. No significantimprovements from baseline to t12 and t36 wereobserved when mean changes in MMSE andADAS-Cog scores were evaluated in the threetherapy groups stratified by apoE e4 allele car-riage versus non-carriage (table III).

Table II. Mean changes in Mini-Mental State Examination (MMSE), Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-

Cog), Activities of Daily Living (ADL), Instrumental Activities of Daily Living (IADL) and Neuropsychiatric Inventory (NPI) score with drug

therapy in completers (values are presented as mean – standard error)

Test Donepezil (n = 488)a Galantamine (n = 94)a Rivastigmine (n = 233)a,b p-Valuec

MMSE (t12–t0) 0.34 – 0.12 (0.0046) -0.26 – 0.27 (NS) 0.26 – 0.17 (NS) NS

MMSE (t36–t12) -0.96 – 0.12 (<0.0001) -0.91 – 0.27 (0.0008) -1.02 – 0.17 (<0.0001) NS

ADAS-Cog (t12–t0) -0.09 – 0.36 (NS) 0.09 – 0.87 (NS) 0.16 – 0.53 (NS) NS

ADAS-Cog (t36–t12) 2.28 – 0.42 (<0.0001) 3.73 – 1.01 (0.0003) 2.52 – 0.62 (<0.0001) NS

ADL (t12–t0) -0.10 – 0.04 (0.01) -0.06 – 0.09 (NS) -0.07 – 0.06 (NS) NS

ADL (t36–t12) -0.33 – 0.05 (<0.0001) -0.41 – 0.11 (0.0002) -0.42 – 0.07 (<0.0001) NS

IADL (t12–t0) -0.21 – 0.05 (<0.0001) -0.21 – 0.12 (0.0739) -0.24 – 0.07 (0.0011) NS

IADL (t36–t12) -0.40 – 0.06d (<0.0001) -0.88 – 0.13d,e (<0.0001) -0.54 – 0.08e (<0.0001) 0.0025

NPI (t12–t0) -0.59 – 0.54 (NS) -1.06 – 1.24 (NS) -1.27 – 0.81 (NS) NS

NPI (t36–t12) 0.37 – 0.56f (NS) 3.63 – 1.28f (0.0046) 1.44 – 0.84 (0.0859) 0.0562

a All p-values in this column were calculated by paired t-test and are versus baseline in t12–t0 analyses, and versus t12 in the t36–t12 analyses.

b One patient without MMSE at t36.

c Chi-squared (w2) test or general linear model procedure.

d Donepezil vs galantamine; p = 0.002.

e Galantamine vs rivastigmine; p = 0.0718.

f Donepezil vs galantamine; p = 0.0587.

NS = not significant; t0 = baseline; t12 = wk 12; t36 = wk 36.

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Discussion

The present investigation is a prospective ob-servational study conducted in a sample of938 patients representative of the clinical scenarioof Italian patients affected by AD; patients werecollected from northern, central and southernItaly following admission to the Italian NationalCP. The three treatment groups (donepezil,galantamine and rivastigmine) comprised pre-dominantly women, although to a lesser extent inthe galantamine group, which had 45.7% malepatients, and the mean age was similar in thethree treatment groups. The majority of patientswere commenced on the lowest daily dose of

AChEI recommended by the manufacturer (5mgfor donepezil, 8mg for galantamine and 3mg forrivastigmine) but, after 4 or 8 weeks, if the drugwas well tolerated, physicians doubled the initialdose according to the CP protocol.

Our data showed a short-term, moderate,cognitive benefit in patients with mild to moder-ate AD treated with donepezil or rivastigmine,but not with galantamine. Globally, no statisti-cal improvements on these outcome measures(MMSE and ADAS-Cog) from baseline tot36 were found with drug therapy. Althoughthe overall cognitive symptoms, as measuredby MMSE and ADAS-Cog scales, worsened by12 and 36 weeks of evaluation, this impairmentwas lower than that attributed to untreated peo-ple with AD in the community.[21,29] In the ab-sence of a cure for AD, a less than expecteddecline in cognitive symptoms is remarkable,given the cost implications of a delay in progres-sion of such symptoms.

Our results are consistent with those of otherreports on Italian patients recruited within theCP, in whom only modest effects of AChEIs oncognitive symptoms were observed. Indeed, atmonth 9, a modest improvement of this type wasevident only in a subgroup of patients withoutconcomitant diseases and who had demonstrateda response at 3 months.[30]

According to recent systematic reviews, thescientific basis for recommending the use ofAChEIs for the treatment of AD is controversial,mainly because of the flawed methodologies ofrandomized, controlled trials and the small clin-ical benefits observed.[12,31] Indeed, according toRaina et al.,[31] ‘‘the treatment of dementia withAChEIs can result in statistically significant butin clinically marginal improvement in measuresof cognition and global assessment of dementia.’’We observed only marginal effects and despitethe large number of patients enrolled, the asso-ciation between drug therapy and categories ofresponders, based either on the MMSE or on theADAS-Cog scale, was found to be not statisti-cally significant.

On the secondary outcome measures (ADL,IADL, NPI), at t36 all groups worsened, losingpoints on the ADL and IADL scales. As for the

01020304050607080

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pond

ers

(%)

Worsened Stable Improved

Classification

a

b

c

0102030405060

Res

pond

ers

(%)

Worsened Stable/improved

Classification

01020304050607080

Res

pond

ers

(%)

No change orimprovement

Improvement≥4 points

Improvement≥7 points

p = 0.37

p = 0.52

p = 0.93

p = 0.34

p = 0.21

Classification

DonepezilGalantamineRivastigmine

Fig. 2. Distribution of responders based on (a, b) Mini-Mental StateExamination (MMSE) score and (c) Alzheimer’s Disease Assess-ment Scale-cognitive subscale (ADAS-Cog) score.

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NPI scale, only the galantamine-treated groupworsened at the last follow-up, although a trendtoward worsening was also seen for the rivas-tigmine-treated group. Moreover, comparing theresults across the treatments, only the galantaminegroup worsened, losing, on average, about oneIADL point from t12 to t36 compared with theother two groups, probably because the galanta-mine group in our study was composed of sub-

jects with the greatest number of risk factors atbaseline. As galantamine was introduced in Italymuch later than the other two AChEIs, and onlyjust before the beginning of this study, physiciansmight have reserved galantamine for sicker, moretreatment-refractory patients, given their lackof familiarity and comfort with the newer drugor because they considered galantamine moreeffective.

Table III. Mean changes in Mini-Mental State Examination (MMSE) and Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-

Cog) [primary outcome measures] scores by apolipoprotein E (apoE) and drug therapy (values are presented as percentages or as mean – SD)

Variable Test Donepezil Galantamine Rivastigmine p-Valuea

No. of patients

t0 541 105 292

t12 517 100 274

t36 491 94 234

apoE NS

e4+ 42.3 38.1 39.0

e4- 56.0 61.9 58.6

missing data 1.7 0 2.4

Primary outcome measures

e4+ MMSE (t0) 19.81 – 4.00 (n = 229) 18.88 – 3.95 (n = 40) 19.47 – 4.16 (n = 114) NS

MMSE (t12) 20.06 – 4.58 (n = 220) 18.92 – 4.87 (n = 37) 19.74 – 4.48 (n = 107) NS

MMSE (t36) 19.03 – 4.57 (n = 207) 18.88 – 5.40 (n = 33) 18.65 – 4.58 (n = 95) NS

e4- MMSE (t0) 20.14 – 4.37 (n = 303) 19.82 – 4.07 (n = 65) 19.74 – 4.46 (n = 171) NS

MMSE (t12) 20.61 – 4.83 (n = 288) 19.76 – 4.21 (n = 63) 20.19 – 4.71 (n = 161) NS

MMSE (t36) 19.87 – 5.12 (n = 275) 18.39 – 4.40 (n = 61) 19.40 – 5.36 (n = 136) NS

e4+ ADAS-Cog (t0) 26.63 – 9.89 (n = 149) 28.57 – 12.56 (n = 31) 28.14 – 10.29 (n = 89) NS

ADAS-Cog (t12) 26.15 – 11.36 (n = 120) 25.01 – 10.98 (n = 23) 27.16 – 10.33 (n = 67) NS

ADAS-Cog (t36) 29.17 – 11.82 (n = 131) 29.65 – 14.24 (n = 22) 29.70 – 11.22 (n = 71) NS

e4- ADAS-Cog (t0) 26.44 – 11.42 (n = 212) 27.70 – 9.83 (n = 40) 27.50 – 11.24 (n = 124) NS

ADAS-Cog (t12) 25.66 – 11.53 (n = 287) 25.38 – 9.95 (n = 52) 26.16 – 10.78 (n = 165) NS

ADAS-Cog (t36) 27.63 – 13.25 (n = 186) 30.74 – 11.67 (n = 36) 29.21 – 12.83 (n = 87) NS

Mean changes in MMSE and ADAS-Cog (completersb,c)

e4+ MMSE (t12–t0) 0.24 – 0.19 -0.41 – 0.47 0.19 – 0.28 NS

MMSE (t36–t12) -1.14 – 0.18 -0.10 – 0.44 -1.23 – 0.26 0.071

ADAS-Cog (t12–t0) -0.40 – 0.57 0.07 – 1.33 1.12 – 0.80 NS

ADAS-Cog (t36–t12) 2.89 – 0.63 4.21 – 1.50 1.51 – 0.88 NS

e4- MMSE (t12–t0) 0.46 – 0.16 -0.18 – 0.33 0.31 – 0.22 NS

MMSE (t36–t12) -0.84 – 0.16 -1.35 – 0.34 -0.85 – 0.23 NS

ADAS-Cog (t12–t0) 0.07 – 0.48 0.12 – 1.14 -0.59 – 0.72 NS

ADAS-Cog (t36–t12) 1.84 – 0.59 3.35 – 1.39 3.21 – 0.89 NS

a Chi-squared (w2) test or general linear model procedure.

b Donepezil (n = 488), galantamine (n = 94), rivastigmine (n = 233).

c One patient in the rivastigmine group without MMSE at t36.

NS = not significant; t0 = baseline; t12 = wk 12; t36 = wk 36; + indicates a carrier; - indicates a non-carrier.

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A possible limitation of our study is the dura-tion of follow-up (36 weeks). According to someauthors, follow-up of longer than 1 year wouldbe necessary and desirable to demonstrate theeffectiveness of drug treatment in patients withAD;[32,33] however, following large numbers ofpatients for long periods in actual clinical prac-tice becomes quite difficult because of the largenumber of patients who drop out.

Direct comparisons of donepezil, galantamineand rivastigmine are relatively few in number.Two studies, a randomized, rater-blinded trialand a randomized, open-label trial, compareddonepezil with galantamine and found no sig-nificant difference between the two drugs in thetreatment of AD.[14,17] In a randomized, multi-national study, Wilkinson et al.[13] compareddonepezil with rivastigmine and found similarimprovements with the two drugs as evaluated onthe ADAS-Cog scale. A recent randomized,open-label trial found pharmacologically induceddifferences between rivastigmine, donepezil andgalantamine in the inhibition of AChE and bu-tyrylcholinesterase activities and protein levelsin the CSF of patients with AD, but the clinicalimplication of these results has yet to be eval-uated.[34] Only two naturalistic studies havecompared the effects of donepezil, rivastigmineand galantamine, and both found no differenceamong the three drugs for the treatment ofAD.[15,16] A major limitation of most of theabove-mentioned studies is the relatively lownumber of patients included, which means defi-nitive conclusions cannot be drawn from them.

Another possible limitation of our study isdosing. The aim of our study was to compare theeffects of the three AChEIs in the clinical sce-narios encountered in the Italian UVAs, whichare distributed over the entire national territory.Physicians generally chose to start therapy withthe lowest dose recommended by manufacturersfor each drug, increasing the dose during treat-ment and reaching the highest dose after 4–8 weeks,as per the general recommendation of the CP. Att36, most patients were taking the highest dose,although a large proportion of patients continuedon a lower dose. Dosing decisions in a ‘real world’clinical practice are subject to many concerns,

including the patient’s health status, drug toler-ability and co-morbidities. Therefore, if a groupof patients in the CP were receiving doses at t36lower than those recommended in clinicaltrials,[35] it is likely that these patients were unableto tolerate higher doses. However, our data re-present a snapshot of clinical practice in AChEItreatment of AD in Italy, and show how resultsobtained under controlled circumstances suchas clinical trials do not fully represent what hap-pens in the ‘real world’. Accordingly, a compar-ison between clinical trials and naturalisticstudies, which considers a variety of factorsthat influence disability in geriatric patients, isrecommended.

Lack of a placebo group, randomization andblinding are other likely limitations of the presentstudy. However, the aim of the study was to com-pare the effectiveness of usual treatment in a largenumber of apoE-genotyped patients with ADwith-in the framework of a national initiative involvingseveral UVAs representative of AD pharma-cotherapy in Italy. In this context, the only com-parison we were able to use was against baseline.

In most studies of the effects of AChEI treat-ment in patients with AD, including the above-mentioned studies that compared donepezil,galantamine and rivastigmine,[13-17] the patientswere not assessed for apoE variants. The avail-able data indicate that apoE e4 carriers have aspecific cognitive domain response to donepezilwhereas non-carriers do not,[36,37] and that thepresence of at least one apoE e4 allele does notaffect response to rivastigmine.[38,39] Contra-dictory results are available for galantamine.[40-43]

No effect of apoE genotype on response to eitherof the three drugs was found in the current study,and the reason for such differences found in otherstudies is at present unclear.

Finally, despite the fact that patients withAD in our study experienced less cognitivedeterioration than is attributed to untreated pa-tients with AD in the community, we did notobserve any significant difference in the effects ofdonepezil, galantamine and rivastigmine on avariety of functional and cognitive parameters ina large number of apoE-genotyped AD patientsover a follow-up period of 36 weeks.

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Conclusions

The key points of this prospective, observa-tional study of treatment with donepezil, ga-lantamine or rivastigmine in a sample of 938patients representative of the clinical scenario ofItalian patients affected by AD were as follows:(i) no statistical improvements in the primaryoutcome measures (MMSE, ADAS-Cog) be-tween baseline and t36 were found with drugtherapy; (ii) at t36 all treatment groups had de-clined, losing on average 1 point on the MMSEand gaining between 2 and 3 points on theADAS-Cog scale; (iii) on the secondary outcomemeasures, all groups worsened, losing from 0.4 to0.5 points on the ADL scale and from 0.6 to 1.0points on the IADL scale. On the NPI scale, therewere no significant differences from baseline ex-cept for the galantamine-treated group whichgained 2.6 points; moreover, a trend towardworsening was also present for the rivastigmine-treated group. When the treatment groups werecompared, the galantamine group worsened sig-nificantly compared with the donepezil group onthe IADL; (iv) no association was found betweendrug therapy and categories of responders, asdetermined by results on either the MMSE or theADAS-Cog instruments; (v) apoE e4 allele didnot influence the effect of therapy with donepezil,galantamine or rivastigmine in patients with AD.

The limitations of this study are its follow-upperiod of only 36 weeks, the fact that the patientsevaluated received lower drug doses than are usedin clinical trials and the lack of randomization ofpatients to the different treatments. The strengthsof this study are that it included a large number ofpatients in a single national study representativeof actual clinical practice for AD pharmacother-apy, it studied the use of three drugs, and itassessed several parameters, including apoEgenotype. Our type of naturalistic study shouldcomplement clinical trials because ‘real world’practice operates in the face of the numerousvariables (e.g. health status and co-morbidities)associated with a complex disease such as AD inelderly people. Thus, this type of study yieldsinformation on the effectiveness of the drugs intheir most usual clinical setting.

Acknowledgements

This work was supported by: the PRRIITT (Programme forIndustrial Research, Innovation and Technology Transfer)programme of the Emilia-Romagna Region (and FondiStrutturali Obiettivo 2); the Italian Ministry of Health Grant‘Progetto Finalizzato Studio delle differenze uomo-donna neimeccanismi patogenetici delle malattie cardiovascolari’; theItalian Ministry of Health Grant ex art 56 533F/B 1; the ItalianMinistry of University and Research (MiUR) PRIN 2006 Pro-ject (#2006061707); the Italian Ministry of Health Grant ‘‘Anintegrated approach to identify functional, biochemical and ge-netic markers in centenarians and Alzheimer’s disease patients’’;the University of Bologna Grant ‘Ricerca FondamentaleOrientata (RFO ex 60%) 2005’; and Roberto and CorneliaPallotti Legacy for Cancer Research Grants to Claudio Fran-ceschi. The authors have no conflicts of interest that are directlyrelevant to the content of this study.

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Correspondence: Aurelia Santoro, PhD, Department ofExperimental Pathology, University of Bologna, ViaS. Giacomo 12, 40126 Bologna, Italy.E-mail: aurelia.santoro@unibo.it

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