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.

Application of Discrete-Event Simulation in Health Technology Assessment: A Cost-Effectiveness Analysis of Alzheimer's Disease Treatment Using Real-World Evidence in Thailand.

OBJECTIVES: Decision-analytic models for Alzheimer's disease (AD) have been advanced to a discrete-event simulation (DES), in which individual-level modeling of disease progression across continuous severity spectra become feasible. This study aimed to apply DES to perform cost-effectiveness analysis of AD treatment in Thailand. METHODS: A data set of Thai AD patients, representing unique demographic and clinical characteristics, was bootstrapped to generate a baseline cohort of 50 000 patients. Each patient was cloned and assigned to donepezil, galantamine, rivastigmine, memantine, or no treatment. Correlated changes in cognitive and behavioral status over time were developed using patient-level data. Treatment effects were obtained from the most recent network meta-analysis. Treatment persistence; mortality; and predictive equations for functional status, costs (Thai baht in 2017), and quality-adjusted life-year (QALY) were derived from country-specific real-world data. RESULTS: From a societal perspective, only the prescription of donepezil to AD patients with all disease-severity levels was found to be cost-effective (incremental cost-effectiveness ratio): 138 524 Thai baht/QALY ($4062/QALY)]. Regardless of whether the treatment-stopping rule when the mini-mental state examination score <10 was introduced, providing early treatment with donepezil to mild AD patients further reduced the incremental cost-effectiveness ratio. Extensive sensitivity analyses indicated robust simulation findings. CONCLUSIONS: Discrete-event simulation greatly enhances the real-world representativeness of decision-analytic models for AD. Donepezil is the most cost-effective treatment option for AD in Thailand and is worth being considered for universal financial coverage. Application of DES in heath technology assessment should be encouraged, especially when the validity of the model is questionable with classical modeling methods.

Predictions of Alzheimer's disease treatment and care costs in European countries.

BACKGROUND: Given the increasing lifespan of the elderly and the higher proportion of older people in the global population, the incidence rate of neurodegenerative diseases is increasing. The aim of this study is to evaluate, by means of computer simulations, developments in the costs of treating and caring for people suffering from Alzheimer's disease (AD) in the EU 28 by 2080, while assuming the introduction of drug administrations at various disease stages. METHODS: Impact analysis leverages a mathematical model that compares five different population development scenarios when introducing different types of drugs to the scenarios but without changing the treatment. Changes in the economic burden are considered as of 2023, when new drugs are expected to enter the market. FINDINGS: The results of the simulations show that by prolonging the length of a person's 'stay' in the Mild, Moderate, or Severe stage, the total cost of care for all persons with AD will increase by 2080. For individual scenarios, the percentage of patients and costs increased as follows: Mild by one year, by 10.61%; Mild by two years, by 17.73%; Moderate by one year, by 16.79%; Moderate by two years, by 34.88%; and Severe by one year, by 23.79%. The change in cost development when prolonging the stay in the Mild cognitive impairment stage (by lowering the incidence by 10%, 30%, or 50%) reduced the cost (by 4.88%, 16.78% and 32.48%, respectively). INTERPRETATION: The results unambiguously show that any intervention prolonging a patient's stay in any stage will incur additional care costs and an increase in the number of persons with AD. Therefore, extending lifespan is important in terms of improving the quality of life of patients, and the introduction of new drugs must consider the additional costs imposed upon society.

Long-term medical costs of Alzheimer's disease: matched cohort analysis.

OBJECTIVES: Medical costs associated with Alzheimer's disease (AD) are characterised by uncertainty and are often presented in a format unsuitable for decision modelling. We set out to estimate long-term medical costs attributable to AD compared to the general population for use in decision modelling. METHODS: We used multiple logistic regressions to generate propensity scores to match 26,951 incident cases of AD with 26,951 people without AD, identified from Danish hospital and medication registries. Costs were available for up to 11 years for each individual, representing costs for 10 years before and 5 years after diagnosis. Generalised estimating equations were employed to investigate the effect of having AD on primary care, medication, hospital and total costs in the matched cohort. We also explored the impact of other socio-economic and demographic factors on healthcare costs. RESULTS: We report costs by year to diagnosis, from 10 years before to 5 after. AD was associated with significantly higher costs, driven by medication and hospital costs, especially around the time of diagnosis. Mean total medical cost was €4996 higher for AD than for the control group in year of diagnosis, after which primary and hospital costs decreased to pre-diagnostic levels. AD had higher attributable primary care costs in years preceding diagnosis. CONCLUSIONS: Reporting AD-attributable costs by year to diagnosis can be useful for use in decision modelling. Medical costs attributed to AD are driven by diagnostic procedures and medication, and the impact of AD on medical costs may not be as high or prolonged as previously suggested.

Diagnosing and treating dementia in German primary and specialized care between 2011 and 2015
.

BACKGROUND: Whilst there was no upturn in detection rate of persons with dementia (PwD) in German general practitioner (GP) practices before 2012, dementia diagnoses markedly increased in 2013 and 2014. OBJECTIVE: (1) Verify the increase of dementia diagnoses in GP practices and neurologist/psychiatrist (NP) practices; (2) examine the subsequent prescription of antidementia drugs. MATERIALS AND METHODS: We performed a retrospective, longitudinal analysis of 874 GP and 141 NP practices collecting clinical data about 220,213 patients who received a dementia diagnosis (ICD-10: G30, F01, F03) between 2011 and 2015. RESULTS: In GP practices, documented dementia diagnoses increased by 73% between 2012 and 2014 (mean 6.4 - 11.1 PwD/practice) and decreased by 26% in 2015 (8.3 PwD/practice). This trend was mostly due to the subgroup of nonspecific (+63%) and vascular dementia (+170%). The upturn has been accompanied by a downturn of the proportion of PwD receiving antidementia drugs (2012: 13.9% vs. 2014: 7.8%). Neither of these trends was found in NP practices. CONCLUSION: The upturn parallels the introduction of monetary incentives for both patients and GPs. It should be examined if these monetary incentives will also lead to an improvement in treatment and care of PwD in the long run.
.

Experimental benznidazole treatment of Trypanosoma cruzi II strains isolated from children of the Jequitinhonha Valley, Minas Gerais, Brazil, with Chagas disease

Trypanosoma cruzi strains from distinct geographic areas show differences in drug resistance and association between parasites genetic and treatment response has been observed. Considering that benznidazole (BZ) can reduce the parasite burden and tissues damage, even in not cured animals and individuals, the goal is to assess the drug response to BZ of T. cruzi II strains isolated from children of the Jequitinhonha Valley, state of Minas Gerais, Brazil, before treatment. Mice infected and treated with BZ in both phases of infection were compared with the untreated and evaluated by fresh blood examination, haemoculture, polymerase chain reaction, conventional (ELISA) and non-conventional (FC-ALTA) serologies. In mice treated in the acute phase, a significant decrease in parasitaemia was observed for all strains. Positive parasitological and/or serological tests in animals treated during the acute and chronic (95.1-100%) phases showed that most of the strains were BZ resistant. However, beneficial effect was demonstrated because significant reduction (p < 0.05%) and/or suppression of parasitaemia was observed in mice infected with all strains (acute phase), associated to reduction/elimination of inflammation and fibrosis for two/eight strains. BZ offered some benefit, even in not cured animals, what suggest that BZ use may be recommended at least for recent chronic infection of the studied region.

Taste-masked and affordable donepezil hydrochloride orally disintegrating tablet as promising solution for non-compliance in Alzheimer's disease patients.

CONTEXT: Manufacturing process and superdisintegrants used in orally disintegrating tablet (ODT) formulation are often time discussed. However, the effect of suitable filler for ODT formulation is not explored thoroughly. OBJECTIVE: The aim of this study was to develop a novel taste masked and affordable donepezil hydrochloride ODT with fast disintegration time and stable to improve medication compliance of Alzheimer's disease patient. METHODS AND MATERIALS: The ODT was manufactured using simple wet-granulation method. Crospovidone XL-10 was used as superdisintegrant and optimization was done by comparing the effect of three grades of lactose monohydrate compound as filler: Starlac®, Flowlac® and Tablettose®. RESULTS AND DISCUSSION: Formulations containing higher amount of colloidal silicon dioxide showed increase in hardness, weight, disintegration time and wetting time after stability study. Formulation E which containing 50% of Starlac® was found with shortest in vitro disintegration time (21.7 ± 1.67 s), in vivo disintegration time (24.0 ± 1.05 s) and in vitro disintegration time in artificial salvia (22.5 ± 1.67 s). Physical stability studies at 40 °C/75% RH for 6 months, Fourier transform infrared spectroscopy analysis and X-ray diffraction results showed that the formulation was stable. The drug-released profile showed that 80% of donepezil hydrochloride was released within 1 min. A single-dose, fasting, four-period, seven-treatment, double-blinded study involving 16 healthy human volunteers was performed to evaluate the palatability of ODT. Formulation VII containing 10 mg of ammonium glycyrrhizinate was able to mask the bitter taste of the drug. CONCLUSION: The product has the potential to be commercialized and it might serve as solution for non-compliance among the Alzheimer's disease patients.

The adoption of pharmaceutical innovation and its impact on the treatment costs for Alzheimer's disease in Taiwan.

BACKGROUND: As the population ages, the number of people living with Alzheimer's disease (AD) has been increasing over time. Between 1999 and 2006, four new AD drugs were approved for insurance coverage in Taiwan. AIMS OF THE STUDY: We investigate the heterogeneous influences of adopting these new drugs on healthcare expenditures. We also evaluate whether the adoption of pharmaceutical innovation creates any "offsetting" effect in the sense that an increase in one component of the health care costs is offset by the decrease in the other components of health care costs. METHODS: AD patients are defined in this study as those who are diagnosed with ICD-9-CM code 331.0. Based on longitudinal insurance claims data, we identify 1,088 AD patients whose first diagnosis occurred between 1997 and 2007. After excluding the period before each patient's AD diagnosis, 4,629 patient-year observations are found to constitute an unbalanced panel data set used in this study. We employ the correlated-random-effects quantile regression (CREQR) method to explicitly control for the unobserved heterogeneity and to consider the heterogeneous influences of adopting new drugs on different points of the conditional distribution function of health expenditures. RESULTS: Our empirical findings are consistent with previous evidence that the adoption of pharmaceutical innovation is costly. To be specific, the expenditure-increasing effect is mainly reflected by the increase in expenditure on drugs in the outpatient sector. In addition, we find evidence of a significant offsetting effect in the sense that new-drug users tend to make less use of inpatient services. As a result, the net effect of adopting pharmaceutical innovation is heterogeneous across AD patients: the use of new drugs is expenditure-increasing for patients whose health care costs are distributed below the 75th quantile; by contrast, the use of new drugs is expenditure-neutral above the 75th quantile, that is, the increase in the drug costs is almost completely offset by the decrease in the inpatient expenditure. DISCUSSION: The adoption of pharmaceutical innovation for treating AD is associated with a significant offsetting effect for higher cost patients. Our results also show that the CREQR method supplements the traditional ordinary least squares (OLS) method to provide interesting information beyond the conditional mean of the distribution. In our study, CREQR estimates suggest that the marginal impact of adopting pharmaceutical innovation on health care costs is heterogeneous across AD patients. IMPLICATIONS FOR HEALTH POLICIES: Given that the impact of adopting new AD drugs on health care costs is not uniform among patients, current payment regulations that impose simple clinical criteria to decide the eligibility of using new drugs, that is, a policy that adopts one size to fit for all, may become an access barrier to realizing the potential benefits of pharmaceutical innovation. IMPLICATIONS FOR FUTURE RESEARCH: Another potential source of the offsetting effect is that adopting new AD drugs may be beneficial to the reduction in the cost of long-term care. This is an important avenue for future research.

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.

Bioactive stilbenes from Vitis vinifera grapevine shoots extracts.

BACKGROUND: Viticultural residues from commercial viticultural activities represent a potentially important source of bioactive stilbenes such as resveratrol. The main aim of the present study was therefore to isolate, identify and perform biological assays against amyloid-ß peptide aggregation of original stilbenes from Vitis vinifera shoots. RESULTS: A new resveratrol oligomer, (Z)-cis-miyabenol C (3), was isolated from Vitis vinifera grapevine shoots together with two newly reported oligostilbenes from Vitis vinifera shoots, vitisinol C (1) and (E)-cis-miyabenol C (2), and six known compounds: piceatannol, resveratrol, (E)-ε-viniferin (trans-ε-viniferin), ω-viniferin, vitisinol C and (E)-miyabenol C. The structures of these resveratrol derivatives were established on the basis of detailed spectroscopic analysis including nuclear magnetic resonance experiments. All the newly reported compounds were tested for their anti-aggregative activity against amyloid-ß fibril formation. Vitisinol C was found to exert a significant activity against amyloid-ß aggregation. CONCLUSION: Vitis vinifera grapevine shoots are potentially interesting as a source of new bioactive stilbenes, such as vitisinol C.

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 a cost-utility model of donepezil for Alzheimer's disease.

OBJECTIVES: The aim of this study was to describe the evolution of a cost-utility model used to inform the UK National Institute for Health and Clinical Excellence's (NICE) most recent decisions on the cost-utility of drug treatments for Alzheimer's disease (AD), and to explore the impact of structural assumptions on the cost-utility results. METHODS: Changes informed by noted limitations of the decision model used in NICE's previous decisions (in 2006) were made cumulatively to the original decision model for donepezil compared with best supportive care (for patients with mild to moderate AD). Deterministic and probabilistic analyses were undertaken for each cumulative change of the model. The expected value of perfect information (EVPI) of parameter estimates and structural assumptions was also calculated. RESULTS: Cumulative changes to the decision model highlighted how the results of the original model (incremental cost-effectiveness ratio of £81,000 per quality-adjusted life-year gained) related to those of the new model (where donepezil was estimated to be cost-saving), mainly due to uncertainty in the incremental cost of donepezil treatment over best supportive care (ranging from -£600 to £3,000 per patient). The partial EVPI analysis reflected this finding where further information on treatment discontinuations and cost parameter estimates were shown to be valuable in terms of reducing decision uncertainty. CONCLUSIONS: Assessing the evolution of the cost-utility model helped to identify and explore structural differences between cohort-based models and is likely to be useful for decision models in other disease areas. This approach makes the structural uncertainty explicit, forcing decision makers to address structural uncertainty in addition to parameter uncertainty.

Genetic testing in combination with preventive donepezil treatment for patients with amnestic mild cognitive impairment: an exploratory economic evaluation of personalized medicine.

OBJECTIVE: To evaluate the cost effectiveness of genetic screening for the apolipoprotein (APOE) ε4 allele in combination with preventive donepezil treatment in comparison with the standard of care for amnestic mild cognitive impairment (AMCI) patients in Canada. METHODS: We performed a cost-effectiveness analysis using a Markov model with a societal perspective and a time horizon of 30 years. For each strategy, we calculated quality-adjusted life-years (QALYs), using utilities from the literature. Costs were also based on the literature and, when appropriate, Ontario sources. One-way and probabilistic sensitivity analyses were performed. Expected value of perfect information (EVPI) analysis was conducted to explore the value of future research. RESULTS: The base case results in our exploratory study suggest that the combination of genetic testing and preventive donepezil treatment resulted in a gain of 0.027 QALYs and an incremental cost of $1,015 (in 2009 Canadian dollars [Can$]), compared with the standard of care. The incremental cost-effectiveness ratio (ICER) for the base case was Can$38,016 per QALY. The ICER was sensitive to the effectiveness of donepezil in slowing the rate of progression to Alzheimer's disease (AD), utility in AMCI patients, and AD and donepezil treatment costs. EVPI analysis showed that additional information on these parameters would be of value. CONCLUSION: Using presently available clinical evidence, this exploratory study illustrates that genetic testing combined with preventive donepezil treatment for AMCI patients may be economically attractive. Since our results were based on a secondary post hoc analysis, our study alone is insufficient to warrant recommending APOE genotyping in AMCI patients. Future research on the effectiveness of preventive donepezil as a targeted therapy is recommended.

Efficacy of cognitive enhancers for Alzheimer's disease: protocol for a systematic review and network meta-analysis.

BACKGROUND: Approximately 35 million people world-wide have Alzheimer's disease and this is projected to nearly double by 2030. Cognitive enhancers, including cholinesterase inhibitors (for example, donepezil, galantamine and rivastigmine) and memantine (N-methyl-D-aspartic acid (NMDA) receptor antagonist) have been approved for the treatment of Alzheimer's disease in many countries. Our objective is to evaluate the comparative effectiveness, safety, and cost of cognitive enhancers for Alzheimer's disease through a systematic review. METHODS/DESIGN: Studies examining the efficacy, safety, and cost of cognitive enhancers compared to placebo, supportive care, and other cognitive enhancers for Alzheimer's patients will be included. The primary outcome is cognition and secondary outcomes include function, behavior, quality of life, safety, and cost. Experimental studies (randomized controlled trials, quasi-randomized controlled trials, controlled clinical trials), quasi-experimental studies (controlled before-after, interrupted time series), and observational studies (cohort, case-control studies) will be eligible for inclusion. Inclusion will not be limited by publication status, time period or language of dissemination.We will search electronic databases (for example, MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, CINAHL, Ageline) from inception onwards. The electronic database search will be supplemented by searching for grey literature (for example, conference proceedings, searches in Google and relevant organization websites). Two reviewers will independently screen the studies for inclusion using the eligibility criteria established a priori and independently extract data. Risk of bias will be assessed using the Cochrane Risk of Bias tool for experimental and quasi-experimental studies and the Newcastle Ottawa Scale for observational studies. If deemed appropriate, meta-analysis and network (that is, indirect comparisons) meta-analysis will be conducted. DISCUSSION: Our systematic review will inform the decision of healthcare providers, policy-makers, Alzheimer's patients and family members about the use of cognitive enhancers, by improving their understanding of the costs, benefits and harms that are associated with these agents. PROSPERO REGISTRY NUMBER: CRD42012001948.