Pharmaceutical Treatment for Alzheimer's Disease and Related Dementias: Utilization and Disparities.

BACKGROUND: Four prescription drugs (donepezil, galantamine, memantine, and rivastigmine) are approved by the US FDA to treat symptoms of Alzheimer's disease (AD). Even modest effectiveness could potentially reduce the population-level burden of AD and related dementias (ADRD), especially for women and racial/ethnic minorities who have higher incidence of ADRD. OBJECTIVE: Describe the prevalence of antidementia drug use and timing of initiation relative to ADRD diagnosis among a nationally representative group of older Americans, and if there are disparities in prevalence and timing by sex and race/ethnicity. METHODS: Descriptive analyses and logistic regressions of Medicare claims (2008-2016) for beneficiaries who had an ADRD or dementia-related symptom diagnosis, or use of an FDA approved drug for AD. We investigate prevalence of use and timing of treatment initiation relative to ADRD diagnosis across time and beneficiary characteristics (age, sex, race/ethnicity, socioeconomic status, comorbidities). RESULTS: Among persons diagnosed with ADRD or related symptoms, 33.3% used an approved drug over the study period. Odds of use was higher among Whites than non-Whites. Among ADRD drug users, 40% initiated use within 6 months of the initial ADRD or related symptoms diagnosis, and 16% initiated prior to a diagnosis. We observed disparities by race/ethnicity: 28% of Asians, 24% of Hispanics, 16% of Blacks, and 15% of Whites initiated prior to diagnosis. CONCLUSIONS: The use of antidementia drugs is relatively low and varies widely by race/ethnicity. Heterogeneity in timing of initiation and use may affect health and cost outcomes, but these effects merit further study.

The cost-effectiveness implications of suboptimal treatment for different severities of Alzheimer's disease in the UK.

OBJECTIVE: This study aims to evaluate the impact of suboptimal treatment, defined in terms of lower population coverage (percentage of total patient population receiving optimal treatment) and delay to treatment on the cost-effectiveness of pharmacological therapies approved for the treatment of different severities of Alzheimer's disease (AD) in the UK. METHODS: A 5-year Markov model was used to simulate transition to full-time care, as delay and coverage were varied for AD patients with mild-to-moderate and moderate-to-severe dementia. The time-varying predictive equations, resource use, utilities, treatment effects and mortality were derived using published sources. RESULTS: For the cohort with moderate-to-severe dementia, cost-effectiveness was optimised when delay was minimised and coverage maximised. For mild-to-moderate dementia, results were similar but varied widely depending on the inputted cost of acetylcholinesterase inhibitors. CONCLUSIONS: The average cost-effectiveness of pharmacological treatments for AD is sensitive to delays to treatment and population coverage. The results of this study can inform future healthcare policy in order to maximise cost-effectiveness of pharmacological therapies for AD. Copyright © 2017 John Wiley & Sons, Ltd.

Trends in Drug Prescription Rates for Dementia: An Observational Population-Based Study in France, 2006-2014.

BACKGROUND: Since the 2011 French guidance updates, cholinesterase inhibitors and memantine are considered optional in the management of dementia and leave physicians free to prescribe based on their clinical expertise. OBJECTIVES: The aims of this study were to analyze the influence of these recent guidance updates on the prescription rates of these drugs and to quantify the impact of potential changes on healthcare expenditures. METHODS: Patients over 65 years old from a representative sample of a national administrative claims database, the French national health insurance database, were retrospectively included from 2006 to 2014. Trends of annual prescription rates were tested using adjusted segmented regression analysis. Drug costs with and without prescribers' behavioral changes were estimated. RESULTS: A total of 119,731 individuals were included and followed during the study period. Among them, 5514 individuals were treated for dementia. According to the unadjusted segmented regression model, there was a significant increase in prescription rates between 2006 and 2010, from 2.23% (95% confidence interval 2.13-2.34) to 2.73% (95% confidence interval 2.62-2.84) of the study population. Since 2011, the trend has reversed with a significant decrease until 2014, from 2.64% (95% confidence interval 2.54-2.75) to 1.92% (95% confidence interval 1.84-2.01). In the multivariate analysis, we also found a gradual decline since 2011, particularly for patients aged 65-69 years and with one or more other chronic diseases. Cost savings associated with prescribers' behavioral changes were estimated at €108 million. CONCLUSION: Drugs prescribed for dementia are on a declining trend with important cost savings, and this was concomitant with guidance updates that left physicians to rely on their clinical expertise while managing dementia.

Cost-effectiveness of donepezil and memantine in moderate to severe Alzheimer's disease (the DOMINO-AD trial).

OBJECTIVE: Most investigations of pharmacotherapy for treating Alzheimer's disease focus on patients with mild-to-moderate symptoms, with little evidence to guide clinical decisions when symptoms become severe. We examined whether continuing donepezil, or commencing memantine, is cost-effective for community-dwelling, moderate-to-severe Alzheimer's disease patients. METHODS: Cost-effectiveness analysis was based on a 52-week, multicentre, double-blind, placebo-controlled, factorial clinical trial. A total of 295 community-dwelling patients with moderate/severe Alzheimer's disease, already treated with donepezil, were randomised to: (i) continue donepezil; (ii) discontinue donepezil; (iii) discontinue donepezil and start memantine; or (iv) continue donepezil and start memantine. RESULTS: Continuing donepezil for 52 weeks was more cost-effective than discontinuation, considering cognition, activities of daily living and health-related quality of life. Starting memantine was more cost-effective than donepezil discontinuation. Donepezil-memantine combined is not more cost-effective than donepezil alone. CONCLUSIONS: Robust evidence is now available to inform clinical decisions and commissioning strategies so as to improve patients' lives whilst making efficient use of available resources. Clinical guidelines for treating moderate/severe Alzheimer's disease, such as those issued by NICE in England and Wales, should be revisited. © 2016 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.

A fixed-dose combination of memantine extended-release and donepezil in the treatment of moderate-to-severe Alzheimer's disease.

Currently available therapies for the treatment of Alzheimer's disease (AD) consist of cholinesterase inhibitors (ChEIs), such as donepezil, and the N-methyl-D-aspartate receptor antagonist memantine. In December 2014, the US Food and Drug Administration approved Namzaric™, a once-daily, fixed-dose combination (FDC) of memantine extended-release (ER) and donepezil for patients with moderate-to-severe AD. The FDC capsule is bioequivalent to the coadministered individual drugs, and its bioavailability is similar when taken fasting, with food, or sprinkled onto applesauce. The combination of memantine and ChEIs in moderate-to-severe AD provides additional benefits to ChEI monotherapy across multiple domains and may delay the time to nursing home admission. A dedicated study of memantine ER compared to placebo in patients on a stable dose of a ChEI found statistically significant benefits on cognition and global status but not functioning. Treatment with memantine ER and donepezil is generally well tolerated, although higher doses of ChEIs are associated with more serious adverse events such as vomiting, syncope, and weight loss. Potential advantages of the FDC include a simpler treatment regimen, reduction in pill burden, and the ability to sprinkle the capsule onto soft foods. Patients who may benefit from the FDC include those with significant dysphagia, a history of poor compliance, or limited caregiver interaction. However, available evidence that these advantages would increase treatment adherence and persistence is conflicting, meaning that the added cost of switching patients from generic options to an FDC may not always be justified.

Drug Product Life-Cycle Management as Anticompetitive Behavior: The Case of Memantine.

A "product hop" involves the substitution of a new formulation of a prescription drug by a pharmaceutical manufacturer for an old version to forestall generic competition. In 2015, for example, Forest Laboratories, the brand-name drug manufacturer of memantine, an Alzheimer's disease treatment, introduced an extended-release version and tried to restrict patient access to the previous version. Product hops can lead to useful incremental innovation but can also have major public health implications by disrupting patients on stable treatment regimens and increasing costs for patients and payers. This commentary reviews alleged anticompetitive product hopping in the case of memantine, which involved proposed conduct that would have left Alzheimer's disease patients with no effective choice but to transition to memantine XR. Policy solutions that can limit anticompetitive product hops include raising the bar for obtaining patents on new drug product formulations and changing automatic generic substitution laws. DISCLOSURES: No outside funding supported this research. To support his work at PORTAL in the summer of 2015, Capati was the recipient of the University of New Hampshire School of Law Rudman Center Public Service Fellowship. Kesselheim's research was supported by Greenwall Faculty Scholars program, the Laura and John Arnold Foundation, and the Harvard Program in Therapeutic Science. In 2013, Kesselheim served as an expert on behalf of a class of individual plaintiffs against Warner Chilcott regarding potential antitrust violations Kesselheim was responsible for concept and design of this commentary. Capati took the lead in data collection and analysis, along with Kesselheim. Capati wrote the manuscript, which was revised by primarily by Kesselheim, along with Capati.

Memantine for treatment of moderate or severe Alzheimer's disease patients in urban China: clinical and economic outcomes from a health economic model.

OBJECTIVE: To estimate the clinical and economic benefits of memantine treatment initiated in moderate Alzheimer's disease (AD) in China, compared with initiation in severe AD only. METHODS: A Markov model with a 5-year time horizon simulated moderate patients' progression through health states. Two groups were compared: patients receiving memantine from the moderate stage (i.e., at model entry), continuing treatment when reaching the severe stage; patients initiating memantine only when they developed severe disease. RESULTS: After 5 years, fewer patients receiving memantine from the moderate stage were severe (49%), dependent (59%) or aggressive (47%) compared with moderate patients who initiated treatment from severe stage only (58, 67 and 55%, respectively). Total cost of care was lower for treatment from moderate stage (67 billion RMB) when compared with treatment from severe stage (73 billion RMB). CONCLUSIONS: In China, AD treatment with memantine from the moderate stage could result in substantial cost savings.

Cost-utility analysis of memantine extended release added to cholinesterase inhibitors compared to cholinesterase inhibitor monotherapy for the treatment of moderate-to-severe dementia of the Alzheimer's type in the US.

OBJECTIVE: This study evaluates the cost-effectiveness of memantine extended release (ER) as an add-on therapy to acetylcholinesterase inhibitor (AChEI) [combination therapy] for treatment of patients with moderate-to-severe Alzheimer's disease (AD) from both a healthcare payer and a societal perspective over 3 years when compared to AChEI monotherapy in the US. METHODS: A phase III trial evaluated the efficacy and safety of memantine ER for treatment of AD patients taking an AChEI. The analysis assessed the long-term costs and health outcomes using an individual patient simulation in which AD progression is modeled in terms of cognition, behavior, and functioning changes. Input parameters are based on patient-level trial data, published literature, and publicly available data sources. Changes in anti-psychotic medication use are incorporated based on a published retrospective cohort study. Costs include drug acquisition and monitoring, total AD-related medical care, and informal care associated with caregiver time. Incremental cost-utility ratio (ICUR), life years, care time for caregiver, time in community and institution, time on anti-psychotics, time by disease severity, and time without severe symptoms are reported. Costs and health outcomes are discounted at 3% per annum. RESULTS: Considering a societal perspective over 3 years, this analysis shows that memantine ER combined with an AChEI provides better clinical outcomes and lower costs than AChEI monotherapy. Discounted average savings were estimated at $18,355 and $20,947 per patient and quality-adjusted life-years (QALYs) increased by an average of 0.12 and 0.13 from a societal and healthcare payer perspective, respectively. Patients on combination therapy spent an average of 4 months longer living at home and spend less time in moderate-severe and severe stages of the disease. CONCLUSION: Combination therapy for patients with moderate-to-severe AD is a cost-effective treatment compared to AChEI monotherapy in the US.

Consumption trends for specific drugs used to treat dementia in the region of Madrid (Spain) from 2002 to 2012.

INTRODUCTION: Analysing drug consumption in large population groups lets us observe consumption trends and compare them between different settings. OBJECTIVE: to analyse the time trends for consumption and costs of specific drugs used to treat dementia in the region of Madrid (Spain) and compare trends by sex and age cohort. METHODS: Descriptive study of cholinesterase inhibitors (N06DA) and memantine (N06DX01) dispensed in Madrid between 2002 and 2012 and covered by the Spain's national health system. Consumption was calculated by analysing changes in DDD (defined daily doses) to find total and yearly increases. The cost was estimated based on DDD price. To compare consumption rates by age and sex, we calculated DDD per 100 inhabitants/day. RESULTS: Between 2002 and 2012, consumption of drugs used to treat dementia increased sixfold. During this period, cholinesterase inhibitors accounted for 76.70% of the drugs consumed and memantine, 23.30%. The estimated cost rose by a by a factor of 5.7 over 11 years (or by a factor of 4 taking into account the use of generic drugs). In 2012, 2.42% of the patients aged 65 or over consumed cholinesterase inhibitors (women 2.82%, men 1.83%) and 0.90% consumed memantine (women 1.10%, men 0.61%). Consumption increased in age cohorts up to 86 to 90 (5.84% for cholinesterase inhibitors and 2.33% for memantine) and declined thereafter. CONCLUSIONS: Consumption of cholinesterase inhibitors and memantine gradually increased, but consumption in 2012 did not reach levels equivalent to dementia prevalence figures. Pharmaceutical expenditure restraint measures may temporarily slow the cost increase temporarily but if the same trend of consumption persists, costs will rise.

Use of cognitive enhancers and associated medical care costs among patients with dementia: a nationwide study in Taiwan.

BACKGROUND: Pharmaceutical therapy for patients with dementia including cholinesterase inhibitors (ChEI) and memantine is covered by Taiwan's National Health Insurance (NHI) but with strict reimbursement criteria. This study compared utilization of selected cognitive enhancers among elderly patients with dementia and estimated associated differences in medical care costs. METHODS: This study used medical claims and pharmacy claims from the NHI Research Database of Taiwan from 2009 to 2011, which included all patients 65 years or older diagnosed with dementia in their outpatient or inpatient claims. Both individual-level and market-level analysis were performed to calculate the average medical costs per person and the share of drug expenditures. Generalized linear models with propensity score adjustment estimated differences in medical care costs by use of selected cognitive enhancers. RESULTS: Users of ChEI had the highest medication and outpatient costs but the lowest inpatient costs among all users of cognitive enhancers. However, annual adjusted total medical care costs per ChEI user were not significantly different from those who used cerebral vasodilators (CBV). In 2011, 52.4% of the elderly with dementia in Taiwan used cognitive enhancers, but among them 88.3% used CBV while 9.2% used ChEI. Among patients with dementia who used at least one cognitive enhancer, the aggregated expenditure as a share of their total drug expenditures was 9.7% in 2011. CONCLUSION: Given that CBV had a much higher utilization rate than ChEI or memantine among elderly people with dementia, the strict reimbursement policy for ChEI and memantine may need to be revisited to increase access to those drugs by patients with dementia in Taiwan.

The impact of memantine in combination with acetylcholinesterase inhibitors on admission of patients with Alzheimer's disease to nursing homes: cost-effectiveness analysis in France.

The costs associated with the care of Alzheimer's disease patients are very high, particularly those associated with nursing home placement. The combination of a cholinesterase inhibitor (ChEI) and memantine has been shown to significantly delay admission to nursing homes as compared to treatment with a ChEI alone. The objective of this cost-effectiveness analysis was to evaluate the economic impact of the concomitant use of memantine and ChEI compared to ChEI alone. Markov modelling was used in order to simulate transitions over time among three discrete health states (non-institutionalised, institutionalised and deceased). Transition probabilities were obtained from observational studies and French national statistics, utilities from a previous US survey and costs from French national statistics. The analysis was conducted from societal and healthcare system perspectives. Mean time to nursing home admission was 4.57 years for ChEIs alone and 5.54 years for combination therapy, corresponding to 0.98 additional years, corresponding to a gain in quality adjusted life years (QALYs) of 0.25. From a healthcare system perspective, overall costs were €98,609 for ChEIs alone and €90,268 for combination therapy, representing cost savings of €8,341. From a societal perspective, overall costs were €122,039 and €118,721, respectively, representing cost savings of €3,318. Deterministic and probabilistic (Monte Carlo simulations) sensitivity analyses indicated that combination therapy would be the dominant strategy in most scenarios. In conclusion, combination therapy with memantine and a ChEI is a cost-saving alternative compared to ChEI alone as it is associated with lower cost and increased QALYs from both a societal and a healthcare perspective.

The impact of Medicare prescription drug coverage on the use of antidementia drugs.

BACKGROUND: Cholinesterase inhibitors and memantine are prescribed to slow the progression dementia. Although the efficacy of these drugs has been demonstrated, their effectiveness, from the perspective of patients and caregivers, has been questioned. Little is known about whether the demand for cholinesterase inhibitors and memantine are sensitive to out-of-pocket cost. Using the 2006 implementation of Medicare Part D as a natural experiment, this study examines the impact of changes in drug coverage on use of cholinesterase inhibitors and memantine by comparing use before and after Medicare Part D implementation among older adults who did and did not experience a change in coverage. METHODS: Retrospective analyses of claims data from 35,102 community-dwelling Medicare beneficiaries in Pennsylvania aged 65 or older. Beneficiaries were continuously enrolled in a Medicare Advantage plan from 2004 to 2007. Outcome variables were any use of donepezil (Aricept(®)), galantamine (Razadyne(®)), rivastigmine (Exelon(®)), tacrine (Cognex(®)), or memantine (Namenda(®)) each year and the number of 30-day prescriptions filled for these drugs. Independent variables included type of drug benefit pre-Part D (No coverage, $150 cap, $350 cap, and No cap as the reference group), time period, and their interaction. Sensitivity analyses were conducted to test if there are differences in use by drug class or if beneficiaries with a diagnosis of dementia pre-Part D experienced an increase in use post-Part D. RESULTS: The No coverage group had a 38% increase in the odds ratio of any use of antidementia medications (P = 0.0008) post-Part D relative to the No cap group. All four coverage groups had significant increases in number of 30-day prescriptions (P < 0.001) over the study period. In adjusted models that included the sub-sample with any use pre-Part D, the No coverage group had a 36% increase in prescriptions (P = 0.002) and the $350 cap group had a 15% increase (P = 0.003) after adjusting for trends in the No cap group. Results from the sensitivity analysis for the sub-sample with a diagnosis of dementia pre-Part D show that each group had significant increases in 30-day prescriptions compared to the No cap control group (P < 0.05). CONCLUSIONS: Use of cholinesterase inhibitors and memantine in our sample increased and a greater increase in use was observed among Medicare beneficiaries who experienced improvements in drug coverage under Medicare Part D.

Evolution of the evidence on the effectiveness and cost-effectiveness of acetylcholinesterase inhibitors and memantine for Alzheimer's disease: systematic review and economic model.

INTRODUCTION: in 2007 the National Institute of Health and Clinical Excellence (NICE) restricted the use of acetylcholinesterase inhibitors and memantine. METHODS: we conducted a health technology assessment (HTA) of the effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine and memantine for the treatment of AD to re-consider and up-date the evidence base used to inform the 2007 NICE decision. The systematic review of effectiveness targeted randomised controlled trials. A comprehensive search, including MEDLINE, Embase and the Cochrane Library, was conducted from January 2004 to March 2010. All key review steps were done by two reviewers. Random effects meta-analysis was conducted. The cost-effectiveness was assessed using a cohort-based model with three health states: pre-institutionalised, institutionalised and dead. The perspective was NHS and Personal Social Services and the cost year 2009. RESULTS: confidence about the size and statistical significance of the estimates of effect of galantamine, rivastigmine and memantine improved on function and global impact in particular. Cost-effectiveness also changed. For donepezil, galantamine and rivastigmine, the incremental cost per quality-adjusted life year (QALY) in 2004 was above £50,000; in 2010 the same drugs 'dominated' best supportive care (improved clinical outcome at reduced cost). This was primarily because of changes in the modelled costs of introducing the drugs. For memantine, the cost-effectiveness also improved from a range of £37-53,000 per QALY gained to a base-case of £32,000. CONCLUSION: there has been a change in the evidence base between 2004 and 2010 consistent with the change in NICE guidance. Further evolution in cost-effectiveness estimates is possible particularly if there are changes in drug prices.

Alzheimer's dementia: budget impact and cost-utility analysis of a combination treatment of a cholinesterase inhibitor and memantine in Switzerland.

QUESTIONS UNDER STUDY: The objective of this study was to estimate the potential budget impact and cost-effectiveness of the combination treatment of a cholinesterase inhibitor and memantine in Switzerland. METHODS: The prevalence of dementia according to European sources and future Swiss population data were used to estimate the number of patients with Alzheimer's dementia in Switzerland. Both direct and indirect costs calculated from Swiss sources were included. Utility estimates and transition probabilities were obtained from the published literature. A Markov model was used for the cost-utility analysis in order to calculate incremental cost-effectiveness ratios from a health care and a societal perspective. RESULTS: Assuming mono treatment (either a cholinesterase inhibitor or memantine), treatment costs would increase from CHF 22.7 million in 2012 to CHF 26.1 million in 2016, the additional yearly treatment costs for the combination treatment (cholinesterase inhibitor and memantine) would be between CHF 1.7 million and CHF 1.9 million. The Markov model compared health care costs of the mono treatment to costs of the combination treatment over five years. From a health care perspective, the combination treatment saved CHF 27,655 per patient over five years and CHF 248,895/quality adjusted life year compared to the mono treatment. CONCLUSIONS: Implementation of the reimbursed combination treatment would incur additional treatment costs of about CHF 10 million over five years. From a health care perspective, the combination treatment would decrease costs over five years by CHF 50 million. Based on long term considerations, the combination treatment was the dominant strategy over the mono treatment.

The effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease (review of Technology Appraisal No. 111): a systematic review and economic model.

BACKGROUND: Alzheimer's disease (AD) is the most commonly occurring form of dementia. It is predominantly a disease of later life, affecting 5% of those over 65 in the UK. OBJECTIVES: Review and update guidance to the NHS in England and Wales on the clinical effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine [acetylcholinesterase inhibitors (AChEIs)] and memantine within their licensed indications for the treatment of AD, which was issued in November 2006 (amended September 2007 and August 2009). DATA SOURCES: Electronic databases were searched for systematic reviews and/or metaanalyses, randomised controlled trials (RCTs) and ongoing research in November 2009 and updated in March 2010; this updated search revealed no new includable studies. The databases searched included The Cochrane Library (2009 Issue 4, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials), MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, PsycINFO, EconLit, ISI Web of Science Databases--Science Citation Index, Conference Proceedings Citation Index, and BIOSIS; the Centre for Reviews and Dissemination (CRD) databases--NHS Economic Evaluation Database, Health Technology Assessment, and Database of Abstracts of Reviews of Effects. REVIEW METHODS: The clinical effectiveness systematic review was undertaken following the principles published by the NHS CRD. We included RCTs whose population was people with AD. The intervention and comparators depended on disease severity, measured by the Mini Mental State Examination (MMSE). INTERVENTIONS: mild AD (MMSE 21-26)--donepezil, galantamine and rivastigmine; moderate AD (MMSE 10-20)--donepezil, galantamine, rivastigmine and memantine; severe AD (MMSE < 10)--memantine. Comparators: mild AD (MMSE 21-26)--placebo or best supportive care (BSC); moderate AD (MMSE 10-20)--donepezil, galantamine, rivastigmine, memantine, placebo or BSC; severe AD (MMSE < 10)--placebo or BSC. The outcomes were clinical, global, functional, behavioural, quality of life, adverse events, costs and cost-effectiveness. Where appropriate, data were pooled using pair-wise meta-analysis, multiple outcome measures, metaregression and mixedtreatment comparisons. The decision model was based broadly on the structure of the three-state Markov model described in the previous technology assessment report, based upon time to institutionalisation, parameterised with updated estimates of effectiveness, costs and utilities. RESULTS: Notwithstanding the uncertainty of our results, we found in the base case that the AChEIs are probably cost saving at a willingness-to-pay (WTP) of £'30,000 per qualityadjusted life-year (QALY) for people with mild-to-moderate AD. For this class of drugs, there is a > 99% probability that the AChEIs are more cost-effective than BSC. These analyses assume that the AChEIs have no effect on survival. For the AChEIs, in people with mild to moderate AD, the probabilistic sensitivity analyses suggested that donepezil is the most cost-effective, with a 28% probability of being the most cost-effective option at a WTP of £'30,000 per QALY (27% at a WTP of £'20,000 per QALY). In the deterministic results, donepezil dominates the other drugs and BSC, which, along with rivastigmine patches, are associated with greater costs and fewer QALYs. Thus, although galantamine has a slightly cheaper total cost than donepezil (£'69,592 vs £'69,624), the slightly greater QALY gains from donepezil (1.616 vs 1.617) are enough for donepezil to dominate galantamine.The probability that memantine is cost-effective in a moderate to severe cohort compared with BSC at a WTP of £'30,000 per QALY is 38% (and 28% at a WTP of £'20,000 per QALY). The deterministic ICER for memantine is £'32,100 per/QALY and the probabilistic ICER is £'36,700 per/QALY. LIMITATIONS: Trials were of 6 months maximum follow-up, lacked reporting of key outcomes, provided no subgroup analyses and used insensitive measures. Searches were limited to English language, The model does not include behavioural symptoms and there is uncertainty about the model structure and parameters. CONCLUSIONS: The additional clinical effectiveness evidence identified continues to suggest clinical benefit from the AChEIs in alleviating AD symptoms, although there is debate about the magnitude of the effect. Although there is also new evidence on the effectiveness of memantine, it remains less supportive of this drug's use than the evidence for AChEIs. The conclusions concerning cost-effectiveness are quite different from the previous assessment. This is because both the changes in effectiveness and costs between drug use and non-drug use underlying the ICERs are very small. This leads to highly uncertain results, which are very sensitive to change. RESEARCH PRIORITIES: RCTs to include mortality, time to institutionalisation and quality of life, powered for subgroup analysis. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Economic evaluation of treatment options in patients with Alzheimer's disease: a systematic review of cost-effectiveness analyses.

INTRODUCTION: Alzheimer's disease (AD) is common among the elderly; it is responsible for 60-80% of all dementia cases. AD is characterized by cognitive decline, behavioural and psychological symptoms, and reductions in functioning and independence. Because of its progressive neurodegenerative nature and unknown aetiology, the burden of AD becomes increasingly significant in an aging population. Estimates indicate that 35.6 million people worldwide suffered from AD in 2010. By 2030 and 2050, this figure is predicted to increase to 65.7 million and 115.4 million, respectively. Costs will also rise along with the increase in the number of people diagnosed with AD. In 2010, the worldwide costs associated with dementia were estimated to be $US604 billion. OBJECTIVE: The objective of this study was to conduct a systematic review of current publications dealing with the pharmacoeconomic factors associated with AD medications and to describe the decision-analytic models used to evaluate long-term outcomes. METHODS: A systematic literature search was performed to identify articles published between 1 January 2007 and 15 July 2010. The search was also based on a previous systematic review, which included literature up to 2007. Articles were included if they were complete and original economic evaluations of AD and if they were comparative in nature. A quality assessment of the included publications was conducted and relevant information was extracted into tables. RESULTS: Seven out of 2067 identified articles were included in this systematic review. Four articles evaluated treatment with donepezil, one with galantamine and two with memantine. The studies were conducted in America, Europe and Asia. Five different groups of medications were compared. The incremental cost-effectiveness ratios (ICERs) for the group of patients treated with donepezil versus no drug treatment ranged from a dominant value to 281, 416.13 euros per quality-adjusted life-year (QALY). Patients treated with donepezil versus placebo showed ICERs with a range from a dominant value (not specified) up to 20, 866.77 euros per QALY. Treatment with memantine in addition to donepezil versus treatment with donepezil alone showed an ICER range from a dominant value to 6818.33 euros per QALY. In comparison with the memantine treatment as an add-on therapy, the ICER of memantine monotherapy versus standard care (without cholinesterase inhibitors [CEIs]) ranged from a dominant value to 63, 087.20 euros per QALY. Finally, the economic evaluation of galantamine in comparison with usual care without any AD drugs showed ICERs ranging from 1894.70 euros to 6953 euros per QALY. CONCLUSION: The seven identified publications included in this review indicate that treatment with CEIs or memantine seems to be reasonable in terms of clinical effects and costs for patients with AD. Depending on different hypotheses, assumptions and variables (e.g. time horizon, discount rates, initial number of patients in different states, etc.) in the sensitivity analyses, treatment with these drugs seems to be primarily a cost-effective strategy or even a cost-saving strategy. Nevertheless, the results generally are associated with a degree of uncertainty. The comparability of the results from the different economic evaluations is limited because of the different assumptions made.

Evaluating the cost effectiveness of donepezil in the treatment of Alzheimer's disease in Germany using discrete event simulation.

BACKGROUND: Previous cost-effectiveness studies of cholinesterase inhibitors have modeled Alzheimer's disease (AD) progression and treatment effects through single or global severity measures, or progression to "Full Time Care". This analysis evaluates the cost-effectiveness of donepezil versus memantine or no treatment in Germany by considering correlated changes in cognition, behavior and function. METHODS: Rates of change were modeled using trial and registry-based patient level data. A discrete event simulation projected outcomes for three identical patient groups: donepezil 10 mg, memantine 20 mg and no therapy. Patient mix, mortality and costs were developed using Germany-specific sources. RESULTS: Treatment of patients with mild to moderately severe AD with donepezil compared to no treatment was associated with 0.13 QALYs gained per patient, and 0.01 QALYs gained per caregiver and resulted in average savings of €7,007 and €9,893 per patient from the healthcare system and societal perspectives, respectively. In patients with moderate to moderately-severe AD, donepezil compared to memantine resulted in QALY gains averaging 0.01 per patient, and savings averaging €1,960 and €2,825 from the healthcare system and societal perspective, respectively.In probabilistic sensitivity analyses, donepezil dominated no treatment in most replications and memantine in over 70% of the replications. Donepezil leads to savings in 95% of replications versus memantine. CONCLUSIONS: Donepezil is highly cost-effective in patients with AD in Germany, leading to improvements in health outcomes and substantial savings compared to no treatment. This holds across a variety of sensitivity analyses.

Cost-effectiveness of memantine in moderate and severe Alzheimer's disease in Norway.

BACKGROUND: The cost-effectiveness of memantine for the treatment of moderate and severe Alzheimer's disease has been assessed in several European countries. Objective of the study was to assess it in Norwegian settings. METHODS: This cost-utility analysis used a Markov modelling approach to simulate the evolution of patients until their need for full-time care (FTC) over a 5-year period. FTC was defined as a patient becoming either dependent or institutionalised. Transition probabilities were estimated using a newly developed predictive equation of time to FTC. Health resource use and utilities were obtained from the Scandinavian Study of Cost and Quality of Life in Alzheimer's Disease study, and mortality was obtained from the Oslo study. Memantine efficacy was based on a meta-analysis of six large trials. The model compared memantine with its alternative in this population, that is no pharmacological treatment or background therapy with acetylcholinesterase inhibitors. The model underwent extensive sensitivity analyses. RESULTS: In Norway, memantine was found to delay the need for FTC by 4.4 weeks compared with standard care and was associated with increased quality-adjusted life years. Memantine was the dominant strategy with cost savings of €3739 (30 041 NOK) per patient. The probability of being the dominant strategy was 98.8%. This result was confirmed across multiple sensitivity analyses. CONCLUSIONS: The model suggests that memantine prolongs time to FTC for no additional cost to the healthcare system and society. It can be regarded as a cost-effective choice in the management of moderate and severe Alzheimer's disease.