CORRESPONDENCE Pharmacoeconomics 2000 Dec; 18 (6): 609-6121170-7690/00/0012-0609/$20.00/0

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Potential Savings in the Cost of Caring forAlzheimer’s DiseaseTreatment with Rivastigmine

The authors reply:In the accompanying correspondence, Linkins

et al. provide a review of our recent pharmacoecon-omic analysis of rivastigmine in the treatment ofAlzheimer’s disease.[1] They suggest a number oflimitations of our analysis.First, Linkins et al. rightly point out that our

estimates of the cost savings attributable to riva-stigmine were determined independent of drug treat-ment cost. This is a limitation we clearly acknow-ledged in our study. We chose this approach for 2reasons. First, at the time our analysis was publish-ed, the US cost of rivastigmine was not available.This is common in pharmacoeconomic studies ofnew drugs that are conducted before the drug islaunched. Secondly, a major objective of this studywas to use an analytical framework that had beenapplied in the UK[2] to estimate the benefits of Alz-heimer’s disease treatment in the US by adjustingfor different treatment patterns and service costs.We provided readers with 2 measures of the

impact of rivastigmine on Alzheimer’s disease pro-gression: the number of days by which disease pro-gression is delayed and total cost savings (inde-pendent of drug treatment cost) resulting from delaysin disease progression. We presented both meas-ures for each baseline cohort – mild Alzheimer’sdisease and moderate Alzheimer’s disease – over 3time horizons (6 months, 1 year and 2 years). Read-ers can, therefore, subtract these cost savings fromany economic measure of the cost of treatment forany given time horizon to estimate the net costs orcost savings associated with treatment with riva-stigmine.Linkins and colleagues also note that we did not

assess the costs associated with the treatment ofadverse events and physician visits for drug dosagetitration. This is consistent with the approach we

used in our study to estimate only the health bene-fits and cost savings resulting from changes in dis-ease progression. These cost savings should thenbe compared with the total costs associated withtreatment with rivastigmine to determine the netcosts or cost savings associated with treatment. Toaddress the comment of Linkins and colleagues,and to provide some context as to the likely cost oftreating adverse effects, we present an overview ofthis issue.The cost of treating adverse events is not likely

to be substantial. Themost common adverse eventsobserved in clinical trials of rivastigmine have beengastrointestinal – specifically, nausea, vomiting andanorexia.[3] It is clear, however, from the results ofthese trials that the incidence of these adverse eventsin patients receiving rivastigmine 6 to 12 mg/daywas an artifact of the trial design; a forced weeklydose titration to the patient’s maximum tolerateddose was required and dose reduction was not al-lowed.[3] This type of dose escalation would not befound in routine clinical practice and differs sub-stantially from the slower titration rate outlined inthe prescribing information for rivastigmine. Oncepatients reached their maintenance dosage in theclinical trials, the incidence of gastrointestinal ad-verse effects was markedly reduced; the incidencewas similar to that in the placebo group.[4] Further-more, as outlined in the package insert,[5] at thetime of intolerance, patients should be instructed todiscontinue treatment for 1 or more doses and thenrestart at the same or next lower dose.Regarding laboratory abnormalities, Corey-Bloom

et al.[3] note that in the rivastigmine clinical trials‘no consistent or clinically significant drug-relatedlaboratory abnormalities were found with regard tovital signs, ECGs or laboratory values (includinghepatic enzymes)’. Therefore, monitoring of organfunction is not required in the product labelling forrivastigmine.In addition, the cost of treating these adverse

events is not likely to be substantial because (i) veryfew patients required treatment for these events;(ii) very few events were rated as severe; (iii) theaverage total duration of these events over the course

of the 6-month trials for patients receiving riva-stigmine was relatively short; and (iv) few patientsdiscontinued treatment because of these adverseevents.[4]Linkins and colleagues also raise the issue of

compliance. In particular, they surmise that adverseevents will lead to decreased compliance and fur-ther affect the potential cost savings.We again wouldlike to note that despite forced dose escalation inthe rivastigmine trials, compliance was very highwith over 90% of patients meeting compliance cri-teria.[4] The slower titration rate stated in the riva-stigmine product labelling might be expected toreduce the number of adverse events experiencedby the patient and increase compliance.Linkins and colleagues then point out that it

is impossible to predict whether clinical benefitsobserved during the 26-week clinical trials wouldpersist at later points in time. We provided 3 time-frames of analysis, thereby allowing readers to ev-aluate the projected cost savings at multiple timeperiods. The model we used in our study assumedthat the efficacy of treatment lasts beyond the 26-week trial period; however, the modelling frame-work also assumed that this effect diminishes overtime. This type of modelling is widely accepted inpharmacoeconomic analysis where only short termclinical data are available.Subsequent to the acceptance and publication of

our paper, Farlow and colleagues[6] reported that inan open-label extension to the US placebo-control-led, phase III trials, the benefits of rivastigminehave been shown to persist for up to 2 years. Inpatients treated with high dose rivastigmine (6 to12 mg/day), the worsening in cognition after 52weeks [by ≈2 points on the Alzheimer’s DiseaseAssessment Scale – Cognitive Subscale (ADAS-Cog)] was half that observed for placebo-treatedpatients (≈4 points) at 26 weeks. In addition, theworsening on the ADAS-Cog at 2 years in this highdose group, was only ≈8 points, which is only halfof that which would be expected in untreated pa-tients. These results provide substantial evidence thatthe clinical benefits observed during the first 26

weeks of treatment are very likely to persist or evenincrease at later points in time.Linkins and colleagues conclude that, ‘. . . to allow

healthcare providers to make informed choices, itis imperative that standards for these analyses aredeveloped and consistently utilised’. While we agreethat some standardisation may be necessary whenthe objective is to provide a direct comparison be-tween 2 alternative treatments, we disagree that stan-dardisation is an imperative prerequisite for health-care providers to make informed decisions. First,healthcare providers are not the only decision-makersin the healthcare decision-making process. Payers,patients and, particularly in the case of Alzheimer’sdisease, patients’ families, are also likely to be in-volved in assessing the value of a particular treat-ment option. The outcome measures of importanceto each of these decision-makers is likely to varysubstantially across groups. Secondly, a strict cost-benefit calculus is unlikely to be the sole criterionupon which a healthcare provider makes a treat-ment decision. Every economic analysis is subjectto numerous limitations and perhaps several inter-pretations. What is important is not that the resultsare standardised, but that any conclusions drawnbased on the results of the analysis acknowledgethe limitations of the analysis and allow each readerto judge and apply the results according to his orher needs.

A. Brett Hauber, PhDEconomist

Parametric Research CorporationWarrington, Philadelphia, USA

Josephine A. Mauskopf, PhDExecutive Director

RTI Health SolutionsResearch Triangle Institute

Research Triangle Park, North Carolina, USA

Edward H. Snyder, Dr. PH.Senior Health EconomistNovartis Pharma A.G.

East Hanover, New Jersey, USA

610 Correspondence

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References1. Hauber AB, GnanasakthyA, Snyder EH, et al. Potential savings

in the cost of caring for Alzheimer’s disease: treatment withrivastigmine. Pharmacoeconomics 2000; 17 (4): 351-60

2. Fenn P, Gray A. Estimating the long term cost savings fromthe treatment of Alzheimer’s disease: a modelling approach.Pharmacoeconomics 1999; 16 (2): 165-74

3. Corey-Bloom J, Anand R,Veach J, for the ENA713B352 StudyGroup. A randomized trial evaluating the efficacy and safetyof ENA317 (rivastigmine tartrate), a new acetylcholinesterare

inhibitor, in patients with mild to moderately severe Alzhei-mer’s disease. Int J Geriatr Psychopharmacol 1998; 1: 55-65

4. Novartis Pharmaceuticals Corporation. Integrated summary ofsafety for Exelon (ENA 713). Basel: Novartis Pharma AG,1997. (Data on file)

5. Exelon® Package Insert. East Hanover (NJ): Novartis Pharma-ceuticals Corporation, 2000

6. FarlowM,Messina J,AnandR.TheAmericanGeriatric Society2000 Annual scientific meeting; 2000 May 17-21; Nash-ville (TN)

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