Parches Rivastigmina

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Assessing the cost-effectiveness of the rivastigminetransdermal patch for Alzheimers disease in the UK

using MMSE- and ADL-based modelsBalazs Nagy1, Alan Brennan1, Agnes Brandtmuller1, Simu K. Thomas2, Sean D. Sullivan3 and Ron Akehurst1

1School of Health and Related Research, University of Sheffield, Sheffield, England2Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA3Pharmaceutical Outcomes Research and Policy Program, University of Washington, Seattle, WA, USACorrespondence to: B. Nagy, E-mail: [email protected]

Objective: Assess long-term cost-effectiveness of rivastigmine patch in Alzheimers disease (AD)management in the UK, using cognitive and functional models based on clinical trial efficacy data.

Methods: Incremental costs and Quality Adjusted Life Years (QALYs) associated with rivastigminepatch and capsule treatment versus best supportive care (BSC) were calculated using two economicmodels, one based solely on Mini-Mental State Examination (MMSE) scores, and one also incorporatingactivities of daily living (ADL) scores. The clinical pathway was populated with data from a clinical trialof rivastigmine patch (9.5 mg/24 h) and capsules (12 mg/day) versus placebo. Costs were based on the UKhealth and social care costs and basic UK National Health Service (NHS) prices. Disease progression wasmodelled beyond the trial period over 5 years using published equations to predict natural decline in ADpatients. Base case costing variables included drugs, clinical monitoring, and institutionalization.

Results: The MMSE model estimated incremental costs per QALY of 10 579 for rivastigmine patch and15 154 for capsule versus BSC. The MMSE-ADL model estimated incremental costs per QALY of 9114for rivastigmine patch and 13 758 for capsules. The main difference between the models was a greaternumber of institutionalized days avoided for rivastigmine versus BSC estimated by the MMSE-ADL

model.Conclusions: Both the MMSE and MMSE-ADL models suggest that rivastigmine patch and capsules arecost-effective treatments versus BSC. Incorporating ADL evidence makes a marginal but importantdifference to estimates in this case. Future economic evaluations of AD treatment should includemeasures of both cognition and functioning. Copyright # 2010 John Wiley & Sons, Ltd.

Key words: Alzheimers disease; rivastigmine; transdermal; cost-effectiveness; NHSHistory: Received 12 November 2009; Accepted 16 April 2010; Published online 15 September 2010 in Wiley Online Library(wileyonlinelibrary.com).DOI: 10.1002/gps.2551

Introduction

An estimated 24.3 million people worldwide sufferfrom dementia, of which the most prevalent form isAlzheimers disease (AD) (Ferri et al., 2005). There iscurrently no cure for AD, although pharmacologicaltherapies may provide symptomatic relief. Socialsupport, home nursing, personal care, communitycare and nursing homes provide the mainstay of non-

pharmacological management (Cummings et al.,2002). The annual per-patient cost of AD in UK isestimated as 16 689 for a person with mild dementialiving in the community, 37 473 for a person withsevere dementia living in the community and 31 296for an institutionalized patient (Knapp and Prince,2007). These costs are expected to rise as the elderlypopulation grows, and the incidence of AD increases(Ferri et al., 2005).

RESEARCH ARTICLE

Copyright # 2010 John Wiley & Sons, Ltd. Int J Geriatr Psychiatry 2011; 26: 483494.


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Cholinesterase inhibitors (ChEIs) are available inoral formulations for the symptomatic treatmentof AD. In 2007, the first transdermal therapy,rivastigmine patch, was approved in Europe for thetreatment of mild-to-moderate AD. The once-daily

rivastigmine patch provides comparable exposure tothe highest dose of rivastigmine capsules (12 mg/day)(Mercier et al., 2007) and improved tolerability, withthree-times fewer reports of nausea and vomitingcompared with older oral treatment (Winblad et al.,2007a).

Numerous studies have estimated the healtheconomic impact of ChEI treatment (Stewart 1997;Stewart et al., 1998; Fenn and Gray, 1999; Jonssonet al., 1999; Neumann et al., 1999; OBrien et al., 1999;Hauber et al., 2000a, 2000b; Garfield et al., 2002; Ikedaet al., 2002; Migliaccio-Walle et al., 2003; Wimo et al.,2003; Loveman et al., 2006). Most previous economic

evaluations of rivastigmine indicate potential costsavings compared with standard care, due to delays ininstitutionalization that offset the costs of drugtreatment (Hauber et al., 2000a, 2000b). The UKsNational Institute for Clinical Excellence (NICE)was established in 1999 to provide guidance on theclinical- and cost-effectiveness of new and existinginterventions to the National Health Service (NHS)of England and Wales. In August 2007, NICErecommended ChEI therapy for the treatment ofmoderate-to-moderately severe AD (Mini-MentalState Examination (MMSE) scores of 1020).

The current standardoutcome measure for modellingclinical outcomes is the MMSE (Folstein et al., 1975).Recently,however, experts have suggested that measuresof cognitive decline alone may not accurately reflectprogression of the aspects of AD that determineprobability of institutionalization (Bavazzano et al.,1998; Bowie et al., 1999; Wolstenholme et al., 2002;Green, 2007). Behavioural and functional deterioration(e.g. loss of ability to perform routine tasks) areconsidered important contributing factors todetermining whether patients require nursing homecare (Desai et al., 2004). Indeed, recent EuropeanMedicines Agency guidelines highlight the importance

of assessments of functional outcomes, recommendingtheir inclusion as a co-primary endpoint (withassessment of cognition) in all clinical trials of ADtreatments (European Medicines Agency, 2008). Inconjunction with cognitive measures such as MMSE,measures of executive and global function, such asactivities of daily living (ADL) assessments, mayprovide a more accurate prediction of time toinstitutionalization than MMSE alone (Hatoum et al.,2009).

The objective of this study was to examine the long-term cost-effectiveness of rivastigmine patch andcapsules based on UK health and social care costs,using a conventional MMSE-based cost-effectivenessmodel, and an additional economic model that also

incorporates ADL data.

Methods

Clinical pathway models

This study utilizes two cost-effectiveness models: onebased on MMSE data alone (MMSE model), and arevised model also incorporating ADL data (MMSE-ADL model). Depending on the model, either MMSEor both MMSE and ADL scores were used to estimatethe number of patients requiring institutionalization.

MMSE scores were also used to quantify impact onhealth-related quality of life (HRQoL).

Data sources

Disease progression was modelled based on MMSEand Alzheimers Disease Cooperative Study-ADL(ADCS-ADL) scores from the pivotal IDEAL(Investigation of transDermal Exelon in ALzheimersdisease) study (Winblad et al., 2007a; Grossberget al., 2009). This 24-week, double-blind, double-

dummy, placebo- and active-controlled trial with a28-week open-label extension compared the efficacyand safety of rivastigmine patch (9.5 mg/24 h) withrivastigmine capsules (12 mg/day) and placebo inpatients with mild-to-moderate AD (Winblad et al.,2007a; Grossberg et al., 2009). A 17.4 mg/24 h patchwas also evaluated, but was not considered here asit is not an approved dose. The clinical pathwaysfor this analysis were populated with data from theIDEAL 24-week double-blind study combined withdata from a further 28-week open-label extensionstudy (rivastigmine patch n 250, rivastigminecapsule n 256). BSC was modelled using theplacebo arm (n 281) of the 24-week double-blindstudy.

Modelling of disease progression

To model the clinical pathway, patients werecategorized over time as being on active rivastigminetreatment or discontinuing treatment and revertingto BSC. Patients also had a probability of death in each


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6-month time period. The IDEAL study provided 6-and 12-month data for placebo and rivastigmine,respectively. As in previous cost-effectiveness analysesof rivastigmine in AD (Fenn and Gray, 1999; Hauberet al., 2000a, 2000b), MMSE scores were used to

model disease progression beyond the clinical trialobservation period.Longer-term MMSE outcomes were quantified

using a published mathematical model (Equation 1)based on a longitudinal study of 719 untreated ADpatients followed for up to 7 years (Mendiondo et al.,2000). This model links an individuals expectedrate of worsening on the MMSE scale to theirprevious time period score, and was employedto predict MMSE decline after a patients lastmeasured outcome. An iterative Mendiondosolution (6-month interval) was applied to theIntent-to-Treat Last Observation Carried Forward

(ITT-LOCF) population in the double-blindphase of the IDEAL study, and the ITT populationin the open-label extension phase. Correctionswere made for potential responder bias for earlydiscontinuations.

Time to 1-point MMSE declineyears

0:00334 MMSE2 0:073MMSE 0:6013(1)

Discontinuation and mortality

During the IDEAL study open-label extension adiscontinuation rate of 19.1% every 6 months wasreported (Grossberg et al., 2009). Discontinuingpatients were presumed to immediately revert to theMMSE score expected if they had been on the BSC armfrom the start of the study. Patients with MMSE scores


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progression data for rivastigmine to estimateTownsend-ADL scores beyond the study period.

Validation of ADCS-ADL disease progression models

MMSE and ADCS-ADL data from the rivastigminearm (n 495) of a 2-year, randomized, clinical trialcomparing rivastigmine and donepezil in AD (Bullocket al., 2005) were used to validate the extrapolationsfrom the IDEAL study. Linear regression using thesedata to describe the relationship between MMSE andADCS-ADL resulted in a slope of 2.0670 0.0415, verysimilar to that arising from our modelling of theIDEAL dataset (2.0645 0.0298).

Utility values

Utility values for both the MMSE and MMSE-ADLmodels were calculated using existing evidencecorrelating HRQoL to MMSE score (Brazier, 2001).Clinical trial data (Corey-Bloom et al., 1998; Rosleret al., 1999) were mapped to health status, as measuredby the Health Utilities Index Version 3 (Furlong andFeeney, 1998). A regression function was derived,indicating that a 1-point deterioration in MMSE isequivalent to a reduction of approximately 0.03 utility(Equation 5) (Brazier, 2001). Quality-Adjusted LifeYears (QALYs) were calculated by applying this

function to the mean MMSE score for each cycle ofobservation, and multiplying by 0.5 to compensate forthe 6-month cycle length.

Utility 0:0982 0:0298 MMSE R2 0:52 (5)

Calculation of cost

The cost of institutionalization in the base-case analysis(for both models) was represented by the healthand social care cost of dementia patients living insupported accommodation in the UK. The sensitivity

analyses considered other types of institutions.Institutionalization costs (29 948 per year; PersonalSocial Services Research Unit, University of Kent, UK,2007) and standard community care costs (CommunityCare package for older people, low cost: 14 300 per year;Curtis and Netten, 2006) were applied consistently,irrespective of disease severity and type of treatment(Netten et al., 2001; Wolstenholme et al., 2002).Informal care costs, in line with the recommendationsof the 2006 NICE analysis (Loveman et al., 2006), were

included in the sensitivity analyses, based on Bell et al.s(2001) estimation of caregiver time stratified by type ofsetting and disease severity (Bell et al., 2001) andmultiplied by the UK minimum wage (5.52 per hour).

Drug acquisition costs of 1020 per annum were

based on basic NHS prices (excluding VAT) (2009).Monitoring costs of 264 per annum (UK NHSreference costs, 2003) were included, assuming twooutpatient visits per patient per year (NICE, 2006a).Discontinuing patients were assumed to incur drug/monitoring costs for a further 3 months, but receive nofurther utility benefit. All costs were updated to 2008 tocompensate for inflation (Curtis, 2008) and futurecosts and health benefits were discounted by 3.5%following UK Treasury Department recommendations(NICE, 2004). All events (e.g. discontinuation) wereassumed to occur halfway through each 6-month cycle.

Incremental cost-effectiveness ratios and net benefit

Following NICE guidance (NICE, 2008), this analysisestimates QALYs and costs for each treatment andcompares the incremental cost per QALY gainedbetween two treatments. A treatment might beconsidered cost-effective if the incremental cost perQALY gained is lower than a threshold willingness-to-pay (lambda) of 20 000 per QALY. Incremental netbenefit can be calculated as lambda incrementalQALY incremental cost. A treatment is considered

cost-effective relative to its comparator if incrementalnet benefit is >0.

Sensitivity analyses

One-way sensitivity analyses examined the effect ofdifferent sources of evidence on the MMSE-basedprobabilities for institutionalization, the impact ofincorporating informal care, and the application oflinear and logistic regressions to elucidate the relation-ship between ADL and MMSE using various populationsof the IDEAL dataset (e.g. open-label/double-blind).

Probabilistic sensitivity analyses investigated theprobability that rivastigmine patch produces greaternet benefit compared with BSC and rivastigminecapsules over a range of willingness-to-pay thresholds.Uncertainty surrounding all model parameters wasdescribed by probability distributions (Table 1), andpropagated through the model using Monte Carlosampling techniques to produce distributions ofexpected costs and QALYs for each treatment group.Uncertainty surrounding the proportion of people at


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Table

1

Uncertaintyinmodelparametersusedforprobabilisticsensitivityanalysesa

Modelparameter

Distribution

Parameter

Value

CovarianceMatrix

Source

Deathrate

Beta

Alpha

141.4

Martinetal.,

1987

Numberof

observations

202

Beta

10.1

Institutionalcost

Normal

Mean

33048

PSSRU,2007

Standarderror

937

Communitycost

Normal

Mean

15848

PSSRU,2006

Standarderror

523

Utilities

Multivariate

normal

Mean(constant)

0.0982

Constant

Slope

ScHARR

Mean(slope)

0.0298

Constant

0.000157854

Slope

0.00000749

0.00000038

Probabilityof

institutionalization

Multivariate

normal

Mean(constant)

0.5116

Constant

Slope

Stewart,1997,

Authors

Mean(slope)

0.0160

Constant

0.011471415

Slope

0.00017999

0.000009

Townsend-ADLMMSE

relationship

Multivariate

normal

Mean(constant)

132140

Constant

Slope

Authors

Mean(slope)

0.4380

Constant

4.317357935

Slope

0.005360524

0.000324

Modelparameter

Distribution

Parameter

Value

Sou

rce

MMSEscore

Normal

Week

0b

26

52

78

104

130

156

182

208

234

260

Win

bladet

al.,2007a,

Nov

artis(dataonfile),

and

patient-level

simulationwith

Mendiondoequation

Mean(patch)

16.7

17.7

17.3

15.8

14.2

12.5

10.8

9.2

7.7

6.4

5.2

Standarderror

0.2

0.3

0.4

0.4

0.5

0.5

0.5

0.5

0.5

0.5

0.5

Mean(capsule)

16.7

17.8

17.1

15.2

13.5

11.7

10.0

8.4

6.9

5.5

4.3

Standarderror

0.2

0.3

0.4

0.4

0.4

0.5

0.5

0.5

0.5

0.5

0.4

Mean(BSC)

16.7

16.6

15.0

13.3

11.6

9.9

8.4

6.9

5.5

4.4

3.5

Standarderror

0.2

0.4

0.4

0.4

0.4

0.4

0.4

0.4

0.4

0.4

0.4

aNumberofiterationsfortheprobabilisticsensitivityanalyses

1000.

bPatient-levelbaselineparameterswereadjustedtorivastigminepatchtoallowallm

odelpopulationstostartfromsameaverageM

MSEscore.TomodelpatchandcapsuleacombinationoftheIDEAL

24-weekdouble-blindandthe28-weekopen-labelpatient-leveldatawasuseduntilWeek52.

TomodelBSCthe24-weekdouble-blinddatawereextrapolatedfromWeek24

usingtheMendiondo

equation.

PSSRU,

PersonalSocialS

ervicesResearchUnit,UniversityofKent,UK;ScHaRR,

SchoolofHealthandRelatedResearch,UniversityofSheffield,UK.


Rivastigmine patch cost-utility in the UK 487


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each MMSE score was characterized using Dirichletdistributions based on the number and percentageof patients attributed to each MMSE score in eachperiod from the disease progression model. Normaldistributions were assigned to the average MMSE

scores of patients in each period based on the patient-level database of the IDEAL study. Two key sources ofuncertaintythe variations of the patient-level MMSEscores in the IDEAL study and uncertainty surround-ing the parameters of the Mendiondo MMSE diseaseprogression equation were taken into account bysampling parameters for the Mendiondo equation andpropagating these through the patient-level databaseusing Monte Carlo simulation.

Results

Cost-effectiveness of rivastigmine patch

Results of the cost-effectiveness analysis using theMMSE and MMSE-ADL models to predict diseaseprogression are shown in Table 2.

The MMSE model predicted incremental costs over 5years of 1174 and 1336 for patients treated with

rivastigmine patch and capsules, respectively, versusBSC. Corresponding incremental benefits wereestimated at 0.1109 and 0.0882 QALYs, respectively.Incremental costs per QALY were 10 579 withrivastigmine patch and 15 154 with capsules,

suggesting that both treatments are cost-effectivecompared with BSC. Comparing patch and capsulesdirectly, the patch appears marginally more beneficial atan incremental 0.0228 QALYs, with similar, thoughslightly lower costs (a difference of162 over 5 years).

The MMSE-ADL model estimates incremental costsover 5 years of 1011 with rivastigmine patch and1213 with capsules, versus BSC. These costs are lowerthan the MMSE-only model (by 14 and 9%,respectively). The QALY differences versus BSC areidentical to those in the MMSE model; hence, theincremental cost-effectiveness ratios of 9114 forrivastigmine patch and 13 758 for capsules suggest

that both treatments would be considered cost-effective. Comparing patch and capsules, the patchis marginally more beneficial, with both the MMSE andMMSE-ADL models estimating moderate 5-year costsavings (162 and 202, respectively). The MMSE-ADL model estimates larger cost savings because thismodel predicts more patients institutionalized at each

Table 2 Cost-effectiveness analysis base casea

Model used Rivastigmine patch Rivastigmine capsule Best supportive careMMSE MMSE-ADL MMSE MMSE-ADL MMSE MMSE-ADL

BenefitsQALYs gained 1.6318 1.6091 1.5209MMSE scores gained 86.2 84.7 78.7Mean survival in years 3.77 3.77 3.77

Costs ()Drug costs 1678 1678 1639 1639 Monitoring costs 533 533 521 521 Institutionalization costs 37 216 47 082 37 619 47 559 39 179 49 353Community care costs 37 698 33 046 37 508 32 821 36 773 31 975Informal care costs

Total costs 77 126 82 339 77 288 82 541 75 952 81 328

MMSE model MMSE-ADL model

Rivastigmine patch versus BSCIncremental cost per QALY gained () 10 579 9114

Incremental cost per MMSE scores gained () 158 136Number of institutional days avoided over 5 years 22.8 26.5

Rivastigmine capsules versus BSCIncremental cost per QALY gained () 15 154 13 758Incremental cost per MMSE scores gained () 226 205Number of institutional days avoided over 5 years 18.0 20.8

Rivastigmine patch versus capsulesIncremental cost per QALY gained () Patch dominates ( 7124) Patch dominates ( 8856)Incremental cost per MMSE scores gained () 106 132Number of institutional days avoided over 5 years 4.8 5.7

aWhere results do not differ between the two models, only one value is reported, for clarity. QALY, Quality Adjusted Life Year; MMSE, Mini-Mental State

Examination; ADL, Activities of Daily Living; BSC, Best Supportive Care.


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level of disease severity, and also has a slightly steeper

slope over the range of moderate-to-severe MMSEscores, resulting in greater cost-related differencesbetween treatments (Figure 1).

Sensitivity analyses

Table 3 summarizes the results of one-way sensitivityanalyses. Results were particularly sensitive to differentsources of probability of institutionalization, with all

other sources (especially non-UK) showing higherprobabilities of institutionalization and steeper slopingrelationships with MMSE than the base case, implyinggreater cost-effectiveness. In each analysis, the MMSE-ADL model resulted in a superior estimate of

incremental cost-effectiveness ratio than the MMSEmodel. The MMSE-ADL model proved insensitive tothe method used to establish the relationship betweenMMSE and ADL scores (using open-label or double-blind data, including/excluding baseline data andlinear/logistic regression).

The results of the probabilistic sensitivity analysesare presented as cost-effectiveness acceptability curves.With the MMSE model, the results suggest a highdegree of certainty that both patch and capsule can beconsidered cost-effective versus BSC (Figure 2). Theprobability of cost-effectiveness at a 20 000 thresholdwas 100.0% for patch (Figure 2a) and 89.7% for

capsule (Figure 2b). It is important to account foruncertainty when comparing patch and capsule. In theprobabilistic sensitivity analyses (Figures 2c and 3c),incremental costs and QALYs between patch andcapsule span every quadrant of the cost-effectivenessplane, showing an overlap of patch and capsule efficacy(and cost-effectiveness). In such a circumstance, cost-effectiveness would be unlikely to drive a decisionbetween patch and capsule, and patient, carer andphysician views and preferences would likely be more

Figure 1 Implied probability of institutionalization related to MMSEscore, using MMSE- (Stewart, 1997) and MMSE-ADL- (McNameeet al., 2001) based predictions for the cost-effectiveness model. MMSE,Mini-Mental State Examination; ADL, Activities of Daily Living.

Table 3 One-way sensitivity analysis for rivastigmine patch versus best supportive care

Sensitivity analysis Costs(rivastigmine, )

Costs(BSC, )

Incrementalcosts ()

QALYs(rivastigmine)

QALYs(BSC)

IncrementalQALYs

Incrementalcost/QALY ()

MMSE model base case(Stewart, 1997)

77 126 75 952 1174 1.6318 1.5209 0.1109 10 579

MMSE-ADL model base case(McNamee et al., 2001)

82 339 81 328 1011 1.6318 1.5209 0.1109 9114

Varying source of probability of institutionalization, MMSE modelUK (Fenn and Gray, 1999) 72 235 71 439 796 1.6318 1.5209 0.1109 7171USA (Hauber et al., 2000b) 89 326 90 338 1012 1.6318 1.5209 0.1109 9124Canada (OBrien et al., 1999) 86 567 87 401 833 1.6318 1.5209 0.1109 7510

Varying the perspective of the analysisInformal care costs included,MMSE model

216 494 217 064 570 1.6318 1.5209 0.1109 5135

Informal care costs included,MMSE-ADL model

210 659 210 357 301 1.6318 1.5209 0.1109 2716

Varying type of regression analysis and patient population to predict Townsend-ADL scores, MMSE-ADL modelLinearOLno baseline 82 178 81 179 999 1.6318 1.5209 0.1109 9006LinearDBall patients 82 412 81 374 1038 1.6318 1.5209 0.1109 9358LogisticOLall patients 82 523 81 505 1019 1.6318 1.5209 0.1109 9183LogisticOLno baseline 82 355 81 346 1009 1.6318 1.5209 0.1109 9097LogitDBall patients 82 412 81 374 1038 1.6318 1.5209 0.1109 9358

MMSE, Mini-Mental State Examination; ADL, Activities of Daily Living; BSC, Best Supportive Care; QALY, Quality Adjusted Life Year; Linear, Linear

regression; Logistic, Logistic regression; OL,Open-Label dataset of the IDEAL study; DB, Double-Blind dataset of the IDEAL study; all patients, observations

made on all patients; no baseline, baseline observations disregarded.




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important. Figure 3 presents the equivalent uncertaintyanalyses for the MMSE-ADL model. The probabilitythat both patch and capsules are cost-effective versusBSC at the 20 000 threshold is even higher than withthe MMSE model.

Discussion

This study explores the effect of incorporatingevidence on functioning, specifically ADL, intocost-effectiveness analysis of AD treatments, and isthe first study to examine the cost-effectiveness ofrivastigmine patch versus BSC. It provides a novelapproach comparing traditional MMSE-based cost-

effectiveness modelling with an analysis incorporatingADL into the health outcomes and cost drivers ofprobability of institutionalization and costs of care.In the MMSE-based analysis, the cost-utility ofrivastigmine versus BSC was estimated at 10 579

per QALY gained for patch, and 15 154 per QALYgained for capsules. The MMSE-ADL model predictshigher institutionalization cost differences and theresulting estimates show rivastigmine as being morecost-effective over a 5-year time horizon versus BSC.The MMSE-ADL model estimates are slightly moresensitive to the evidence used to quantify probabilityof institutionalization than the MMSE-only model(Table 2). Both models estimated costs per QALYlower than the frequently referenced NICE threshold

Figure 2 Results of probabilistic sensitivity analyses for the MMSE model: (A) rivastigmine patch versus BSC; (B) rivastigmine capsule versus BSC; (C)rivastigmine patch versus capsule.


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range (20 00030 000 per QALY), suggesting thatboth the rivastigmine patch and rivastigmine capsulesmight be considered cost-effective treatments for ADcompared with BSC.

There are several possible limitations to this analysis.

Firstly, only one explanatory variable (MMSE score)was included in the regression analyses relating ADLscores to MMSE. Other patient characteristics (e.g. age,sex) were not included as they could not beincorporated in the cost-effectiveness model, whichprimarily characterizes patients according to MMSE.However, as the randomization process of the clinicaltrial produced groups of patients with very similarbaseline characteristics between the study arms, thismay not have biased our findings. Second, these

regression analyses were based on relatively short-termcross-sectional data. It was, therefore, not possible totest the validity of the MMSEADL relationship over alonger time scale. Long-term (5-year) ADL and MMSEevidence to validate the ADL-based predictions would

be useful. A third limitation is that our mapping ofthe ADCS-ADL scale to the Townsend-ADL scale wasbased on a qualitative approach which we are notable to validate empirically. A survey of a patientpopulation using both scales would be helpful for thispurpose. Fourth, the analyses incorporating ADL datafocussed mostly on estimation of institutionalization,the most influential predictor of AD costs. Furtherevidence on the relationships between ADL and otherinputs, especially utilities, community care costs, and

Figure 3 Results of probabilistic sensitivity analyses for the MMSE-ADL model: (A) rivastigmine patch versusBSC; (B) rivastigmine capsule versusBSC;(C) rivastigmine patch versus capsule.




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informal care costs, would enable refinement of thecost-effectiveness estimates.

In modelling long-term cost-effectiveness in AD,several assumptions need to be made regardinglong-term disease progression and probability of

institutionalization. The key assumption in ouranalysis is that the Mendiondo natural history modelof disease progression applies to both the BSC arm andthe rivastigmine arms in the model (Mendiondo et al.,2000). An alternative used in previous modellingexercises is Markov modelling of MMSE subgroups topredict transitions over the long-term, based on theplacebo arm of the trial. However, using this approachwith the placebo arm of the IDEAL dataset produced along-term prediction of almost no disease progressionover time (because mean MMSE change for thesepatients over 24 weeks was very small). This was socontradictory to clinical and real-life experience as to

be an implausible modelling approach.Published estimates of probability and time to

institutionalization vary greatly and there is notheoretical reason why the relationship should belinear. The base case assumption used here is the mostrecent available for the UK, but is nearly 10 years old.The use of alternative (non-UK and nonlinear) datasources (OBrien et al., 1999; Hauber et al., 2000b)alters the costutility ratio estimates (Table 3),although no analysis resulted in a costutility higherthan the NICE threshold. In addition, a recent analysissuggested that the public sector may meet 70% of

institutional care costs (NICE, 2006b). However, inreality many patients/carers cover varying degrees ofthese costs. More up-to-date evidence on the UKprobability and timing of institutionalization related toMMSE and ADL, and on the proportion of costs paidby public sector and by individuals would be useful fordecision makers. Similarly, while the relationshipbetween utilities and MMSE is not necessarily linear,no better source of evidence to correlate utility toMMSE score was available. However, the Brazierequations used in this analysis seemed reasonably wellestablished (R2 0.52; p< 0.001).

Several factors are excluded from the calculations.

Costs and benefits incurred by carers were not includedin our central analysis. When informal care costs wereincluded in the model, the costutility ratio changed infavour of rivastigmine. This is largely because incommunity settings, informal caregiver time and costsare related to disease severity, whilst in institutionalsettings informal caregiver time and costs areindependent of disease severity. The model estimatesmarginally higher disease severity for patients in theBSC arm compared with rivastigmine, so BSC arm

patients are estimated to receive more informal careduring the period that they are in a community setting.This in turn reduces the estimated difference incosts between the treatment arms. We excluded anypotential reduction of caregiver workload related

directly to the patch, because although it is conceivedof as a once-daily, easy-to-administer treatment forAD, and is preferred by most caregivers to capsules(Winblad et al., 2007b), there was no definitivequantified evidence on caregiver time saved to factorthis preference into either the quality of life or the costsside of a carer-based cost-effectiveness analysis. Alsoexcluded were mild ChEI-associated side effects such asnausea and vomiting, because no direct evidence onthe HRQoL or costs of such adverse events wasavailable. However, withdrawals due to side effects areincluded in the discontinuation rates for both arms.

The model framework presented here could be

extended to assess other questions on cost-effectivenessin AD. Analyses using inputs specific to non-UKcountries could determine whether rivastigmine patchcould provide similar savings in the USA andelsewhere. This analysis compares rivastigmine patchagainst rivastigmine capsules and BSC. Further workanalysing rivastigmine patch versus other ChEIs wouldbe of interest. However, without access to individual-level data for other ChEIs, a detailed analysis would bedifficult. It would also be an indirect mixed treatmentcomparison, as head-to-head study data are notavailable.

In conclusion, future health economic analysesshould move beyond the exclusive use of cognitiveoutcomes such as MMSE to model cost-effectiveness,and incorporate measures of function and behaviouraldeterioration. Collection of additional data on MMSE,ADL, QoL of patients and/or carers, carer time andbehavioural and psychological symptoms of dementia,and subsequent further research on the relationshipsbetween MMSE, ADL, disease progression, probabilityof institutionalization, utilities and costs would bewelcomed by analysts and decision makers. In thisanalysis, both the MMSE and MMSE-ADL modelssuggest that rivastigmine patch and capsules can be

considered cost-effective treatments for AD versus BSCin the UK context. The MMSE-ADL model indicatedsomewhat greater estimated cost-effectiveness,primarily due to a greater number of institutionalizeddays avoided with rivastigmine compared with BSC.Incorporation of ADL-based evidence into cost-effectiveness analysis should be a priority. Decisionmakers in a variety of organizations and countries nowuse cost-effectiveness analyses such as this one to helpdetermine reimbursement decisions and priorities.


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Recent NICE guidance concluded that the threeacetylcholinesterase inhibitors donepezil, galantamineand rivastigmine are recommended as options in the

management of patients with Alzheimers disease ofmoderate severity (NICE, 2009). The health economicanalysis presented here is broadly in line with theseNICE recommendations, suggesting that policy-makers and clinicians should consider rivastigminepatch and capsule as cost-effective interventions for thetreatment of moderate AD in England and Wales.

Conflict of interest

None declared.

Acknowledgements

This study was supported by Novartis PharmaceuticalsCorporation, East Hanover, NJ, USA. Alpha-PlusMedical Communications Ltd (UK) provided editorialassistance with the production of the manuscript. Theauthors gratefully acknowledge John Brazier for hisprevious research on utility valuation, and PatriciaSacco for her assistance in the submission of this paper.

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Key Points

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Future economic evaluations of AD treatmentshould include measures of both cognition andfunctioning.




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