Cumulative Anticholinergic Burden and its Predictors among Older Adults with Alzheimer's Disease Initiating Cholinesterase Inhibitors.

BACKGROUND: Cumulative anticholinergic burden refers to the cumulative effect of multiple medications with anticholinergic properties. However, concomitant use of cholinesterase inhibitors (ChEIs) and anticholinergic burden can nullify the benefit of the treatment and worsen Alzheimer's disease (AD). A literature gap exists regarding the extent of the cumulative anticholinergic burden and associated risk factors in AD. Therefore, this study evaluated the prevalence and predictors of cumulative anticholinergic burden among patients with AD initiating ChEIs. METHODS: A retrospective longitudinal cohort study was conducted using the Medicare claims data involving parts A, B, and D from 2013 to 2017. The study sample included older adults (65 years and older) diagnosed with AD and initiating ChEIs (donepezil, rivastigmine, or galantamine). The cumulative anticholinergic burden was calculated based on the Anticholinergic Cognitive Burden scale and patient-specific dosing using the defined daily dose over the 1 year follow-up period after ChEI initiation. Incremental anticholinergic burden levels were dichotomized into moderate-high (sum of standardized daily anticholinergic exposure over a year (TSDD) score ≥ 90) versus low-no (score 0-89). The Andersen Behavioral Model was used as the conceptual framework for selecting the predictors under the predisposing, enabling, and need categories. A multivariable logistic regression model was used to evaluate the predictors of high-moderate versus low-no cumulative anticholinergic burden. A multinomial logistic regression model was also used to determine the factors associated with patients having moderate and high burdens compared to low/no burdens. RESULTS: The study included 222,064 older adults with AD with incident ChEI use (mean age 82.24 ± 7.29, 68.9% females, 83.6% White). Overall, 80.48% had some anticholinergic burden during the follow-up, with 36.26% patients with moderate (TSDD scores 90-499), followed by 24.76% high (TSDD score > 500), and 19.46% with low (TSDD score 1-89) burden categories. Predisposing factors such as age; African American, Asian, or Hispanic race; and need factors included comorbidities such as dyslipidemia, syncope, delirium, fracture, pneumonia, epilepsy, and claims-based frailty index were less likely to be associated with the moderate-high anticholinergic burden. The factors that increased the odds of moderate-high burden were predisposing factors such as female sex; enabling factors such as dual eligibility and diagnosis year; and need factors such as baseline burden, behavioral and psychological symptoms of dementia, depression, insomnia, urinary incontinence, irritable bowel syndrome, anxiety, muscle spasm, gastroesophageal reflux disease, heart failure, and dysrhythmia. Most of these findings remained consistent with multinomial logistic regression.  CONCLUSION: Four out of five older adults with AD had some level of anticholinergic burden, with over 60% having moderate-high anticholinergic burden. Several predisposing, enabling, and need factors were associated with the cumulative anticholinergic burden. The study findings suggest a critical need to minimize the cumulative anticholinergic burden to improve AD care.

Reversal of neuromuscular block: what are the costs?

Patients requiring neuromuscular block for anaesthesia have a higher risk of adverse postoperative outcomes. The choice of reversal drug and its corresponding dose is critical for improving clinical outcomes. Although drug costs are higher for sugammadex relative to neostigmine, additional factors need to be considered when choosing one drug over the other. New data from a recent study in the British Journal of Anaesthesia indicate cost advantages for sugammadex in low-risk and ambulatory patients, but for neostigmine in high-risk patients. These findings highlight the need to take local and temporal factors into consideration in addition to clinical effectiveness when performing cost analyses for administrative decision-making.

Dysphagia Risk in Patients Prescribed Rivastigmine: A Systematic Analysis of FDA Adverse Event Reporting System.

BACKGROUND: Dysphagia has been reported as an adverse event for patients receiving rivastigmine for Alzheimer's disease (AD) treatment. OBJECTIVE: The purpose of this study was to determine the association between dysphagia and the usage of rivastigmine by using the pharmacovigilance data from the FDA Adverse Event Reporting System (FAERS). METHODS: The risk of dysphagia in patients who took rivastigmine was compared with those of patients who took other medications. In addition, this study sought to determine if the dysphagia risk was influenced by sex, age, dosage, and medication routes of administration. RESULTS: When compared to patients prescribed donepezil, galantamine, or memantine, individuals prescribed rivastigmine were almost twice as likely to report dysphagia as an adverse event. The dysphagia risk in individuals prescribed rivastigmine is comparable to individuals prescribed penicillamine but significantly higher than clozapine, drugs of which have been previously shown to be associated with elevated dysphagia likelihood. Individuals older than 80 were 122% more likely to report having dysphagia after being prescribed rivastigmine than patients that were 50-70 years of age. Oral administration of rivastigmine was associated with approximately 2 times greater likelihood of reporting dysphagia relative to users of the transdermal patch. In addition, dysphagia showed higher association with pneumonia than other commonly reported adverse events. CONCLUSION: Patients prescribed rivastigmine were at greater risk of reporting dysphagia as an adverse event than patients prescribed many other medicines. This increase in dysphagia occurrence may be attributed to the dual inhibition of both acetylcholinesterase and butyrylcholinesterase.

Risk of Serious Adverse Events Associated With Individual Cholinesterase Inhibitors Use in Older Adults With Dementia: A Population-Based Cohort Study.

BACKGROUND AND OBJECTIVE: Cholinesterase inhibitors (ChEIs) are used as first-line pharmacotherapy to manage dementia. However, there are limited data regarding their relative safety. This study evaluated the risk of serious adverse events (SAEs) associated with individual ChEIs in older adults with dementia and also examined sex-based and dose-based effects on this risk. METHODS: This was a retrospective cohort study using 2013-2015 US Medicare claims data involving Parts A, B, and D. Patients aged ≥ 65 years with a dementia diagnosis and incident use of the ChEIs, namely donepezil, galantamine, or rivastigmine, were included. The primary outcome of interest was SAEs defined as emergency department visits, inpatient hospitalizations, or death within 6 months of ChEI initiation. Multivariable Cox proportional hazards regression with propensity score (PS) as a covariate and inverse probability of treatment weighting generated using generalized boosted models was used to assess the risk of SAEs across individual ChEIs. RESULTS: The study included 767,684 older adults with dementia who were incident new users of ChEIs (donepezil 79.42%, rivastigmine 17.67%, galantamine 2.91%). SAEs were observed in 15.5% of the cohort within 6 months of ChEI prescription. Cox regression model with PS as covariate found that patients prescribed rivastigmine (adjusted hazard ratio [aHR] 1.12; 95% CI 1.03-1.33) and galantamine (aHR 1.51; 95% CI 1.24-1.84) were at increased risk of SAEs compared with patients on donepezil. Stratified analyses revealed that rivastigmine was associated with an 18% increased risk for SAEs in females (aHR 1.18; 95% CI 1.06-1.31), and galantamine was associated with a 71% increased risk in males (aHR 1.71; 95% CI 1.17-2.51) compared with donepezil. High and recommended index doses of rivastigmine and galantamine were associated with an increased risk of SAEs compared with donepezil. The findings were consistent in sensitivity analyses. CONCLUSION: The study found that the risk of SAEs varied across individual ChEIs, with sex and dose moderating these effects. Therefore, these moderating effects should be carefully considered in personalizing dementia care.

Risk of overactive bladder associated with cholinesterase inhibitors in dementia.

BACKGROUND: Although cholinesterase inhibitors (ChEIs) are the primary treatment for dementia, they are associated with overactive bladder (OAB), necessitating antimuscarinic use. Limited data exist regarding the risk of OAB across individual ChEIs in dementia. This study evaluated the risk of OAB associated with individual ChEIs in older adults with dementia. METHODS: This was a new user retrospective cohort study using Medicare claims data involving Parts A, B, and D claims dataset from 2013 to 2015. The study included older adults (aged 65 and older) with a diagnosis of dementia using donepezil, galantamine, or rivastigmine. New ChEI claims were identified with a 6-month baseline washout period. Patients with OAB diagnosis or any antimuscarinic or mirabegron use in the baseline period were excluded. The primary outcome of interest was OAB diagnosis or prescription of antimuscarinics or mirabegron within 6 months of ChEI initiation. Multivariable cox proportional hazards regression with propensity scores (PS) as covariates and inverse probability of treatment weighting generated using generalized boosted models was used to assess the risk of OAB among donepezil, galantamine, and rivastigmine users. RESULTS: The study included 524,975 older adults with dementia who were incident users of ChEIs (donepezil 80.72%, rivastigmine 16.41%, galantamine 2.87%). Overall, OAB diagnosis/antimuscarinic/mirabegron prescription was observed in 5.07% of the cohort within 6 months of ChEIs prescription. The Cox regression model with PS as covariate approach found that donepezil use increased the risk of OAB compared to rivastigmine (aHR, 1.13; 95% CI, 1.08-1.28; p < 0.0001). However, there was no differential risk of OAB between galantamine and rivastigmine. The findings were consistent with the generalized boosted models. CONCLUSIONS: The study found that the risk of OAB varies across individual ChEIs with an increased risk of OAB with donepezil compared to rivastigmine. The study findings suggest the need to understand and manage medication-related morbidity in older adults with dementia.

Antipsychotic Initiation Among Older Dementia Patients Using Cholinesterase Inhibitors: A National Retrospective Cohort Study.

BACKGROUND: Evidence regarding the initiation of antipsychotic medications across individual cholinesterase inhibitors (ChEIs) to manage the behavioral symptoms of dementia is lacking. OBJECTIVES: This study compared the risk of initiation of antipsychotic medications among older adults with dementia treated with the ChEIs donepezil, rivastigmine, or galantamine. METHODS: This retrospective cohort study used multiyear (2013-2015) Medicare claims data involving Parts A, B, and D. The study sample included community-dwelling older adults (aged ≥ 65 years) with a diagnosis of dementia. The study identified new users of ChEIs and followed them for up to 180 days for antipsychotic initiation. The ChEIs included donepezil, rivastigmine, and galantamine, whereas antipsychotics included typical and atypical agents. Donepezil was used as the reference category as it is the most commonly used ChEI and only acts on acetylcholinesterase, whereas both rivastigmine and galantamine have dual mechanisms of action. Multivariable Cox proportional hazards regression compared the risk of and time to antipsychotic initiation among the three ChEIs, adjusting for other risk factors. RESULTS: The study cohort consisted of 178,441 older adults with dementia who were new users of ChEIs. A total of 23,433 (15.14%) donepezil users, 4114 (19.04%) rivastigmine users, and 324 (15.77%) galantamine users initiated antipsychotics. The mean time to antipsychotic initiation among patients who received antipsychotics was 109.29 ± 69.72 days for donepezil users, 96.70 ± 71.60 days for rivastigmine users, and 104.15 ± 72.53 days for galantamine users. The Cox regression analysis showed that rivastigmine (adjusted hazard ratio [aHR] = 1.27; 95% confidence interval [CI], 1.20-1.34) was significantly associated with antipsychotic initiation compared with donepezil, whereas no significant difference was observed between galantamine and donepezil (aHR = 0.98; 95% CI, 0.81-1.20). CONCLUSION: The study found a 27% increased risk of antipsychotic initiation among users of rivastigmine compared with donepezil users. There was no difference between galantamine and donepezil for antipsychotic initiation. Although the limitations of the study should be considered, the results suggest that donepezil or galantamine may be more appropriate treatments for older patients with dementia, to minimize antipsychotic use.

Sugammadex versus neostigmine for routine reversal of rocuronium block in adult patients: A cost analysis.

STUDY OBJECTIVE: This report analyzes the comparative costs, efficacy and side effects of a newer, more expensive reversal drug, sugammadex, with its generic counterpart, neostigmine combined with glycopyrrolate, or no reversal agent when used routinely to reverse rocuronium-induced neuromuscular blockade in adult patients. DESIGN: Cost analysis. METHODS: We constructed a decision model to analyze the costs associated with the choice of reversal drug and differences in reversal time, occurrence of postoperative nausea or vomiting (PONV), and residual blockade requiring unplanned postoperative mechanical ventilation (UPMV). We selected variables that demonstrated meaningful differences in meta-analyses of published studies and/or had significant associated costs. We used data from local hospital system information, meta-analysis of published studies, and the general literature to construct base-case scenarios and sensitivity analyses. We performed the analysis from the perspective of a single hospital system. Costs were in 2019 U.S. dollars. RESULTS: Cost analysis suggested that reversal with sugammadex is preferable to neostigmine or no reversal drug when operating room (OR) time was valued at ≥$8.60/min (base case $32.49/min). Net costs of sugammadex were less than no treatment or neostigmine reversal when the probability of UPMV exceeded 0.019 and 0.036, respectively. Neither sugammadex nor neostigmine reversal was preferable to no treatment in a base-case analysis that considered the effect of the reversal agent on only drug and PONV costs, disregarding costs of OR time or UPMV. CONCLUSIONS: Routine reversal with sugammadex is preferable to choosing neostigmine or no reversal drug when accounting for potential savings in OR time. Sugammadex might also be a reasonable choice for patients at high risk of UPMV. If the cost of OR time is not considered, the analysis does not support the routine use of sugammadex in patients with perceived increased risk or solely to reduce PONV.

Impact of deprescribing AChEIs on aggressive behaviors and antipsychotic prescribing.

INTRODUCTION: We evaluated the impact of deprescribing acetylcholinesterase inhibitors (AChEIs) on aggressive behaviors and incident antipsychotic use in nursing home (NH) residents with severe dementia. METHODS: We conducted a retrospective study of Medicare claims, Part D, Minimum Data Set for NH residents aged 65+ with severe dementia receiving AChEIs in 2016. Aggressive behaviors were measured using the aggressive behavior scale (ABS; n = 30,788). Incident antipsychotic prescriptions were evaluated among antipsychotic non-users (n = 25,188). Marginal structural models and inverse probability of treatment weights were used to evaluate associations of AChEI deprescribing and outcomes. RESULTS: The severity of aggressive behaviors was low at baseline (mean ABS = 0.5) and was not associated with deprescribing AChEIs (0.002 increase in ABS, P = .90). Incident antipsychotic prescribing occurred in 5.1% of residents and was less likely with AChEI deprescribing (adjusted odds ratio = 0.52 [0.40-0.68], P <.001]). DISCUSSION: Deprescribing AChEIs was not associated with a worsening of aggressive behaviors or incident antipsychotic prescriptions.

Risk for Health Events After Deprescribing Acetylcholinesterase Inhibitors in Nursing Home Residents With Severe Dementia.

BACKGROUND/OBJECTIVE: Reevaluation of the appropriateness of acetylcholinesterase inhibitors (AChEIs) is recommended in older adults with severe dementia, given the lack of strong evidence to support their continued effectiveness and risk for medication-induced adverse events. We sought to evaluate the impact of deprescribing AChEIs on risk of all-cause events (hospitalizations, emergency department visits, and mortality) and serious falls or fractures in older nursing home (NH) residents with severe dementia. DESIGN: Analysis of 2015 to 2016 data from Medicare claims, Part D prescriptions, Minimum Data Set (MDS) version 3.0, Area Health Resource File, and Nursing Home Compare. Marginal structural models with inverse probability of treatment weights were used to evaluate the association of deprescribing AChEIs and all-cause negative events as well as serious falls or fractures. SETTING: US Medicare-certified NHs. PARTICIPANTS: Nonskilled NH residents, aged 65 years and older, with severe dementia receiving AChEIs within the first 14 days of an MDS assessment in 2016 (n = 37 106). RESULTS: The sample was primarily white (78.7%), female (75.5%), and aged 80 years or older (77.4%). Deprescribing AChEIs was associated with an increased likelihood of all-cause negative events in unadjusted models (odds ratio [OR] = 1.17; 95% confidence interval [CI] = 1.11-1.23; P < .01), but not in fully adjusted models (adjusted OR [aOR] = 1.00; 95% CI = 0.94-1.06; P = .94). By contrast, deprescribing was associated with a reduced likelihood of serious falls or fractures in unadjusted models (OR = 0.59; 95% CI = 0.52-0.66; P < .001) and remained significant in adjusted models (aOR = 0.64; 95% CI = 0.56-0.73; P < .001). CONCLUSION: Deprescribing AChEIs was not associated with a significant increase in the likelihood for all-cause negative events and was associated with a reduced likelihood of falls and fractures in older NH residents with dementia. Our findings suggest that deprescribing AChEIs is a reasonable approach to reduce the risk of serious falls or fractures without increasing the risk for all-cause events. J Am Geriatr Soc 68:699-707, 2020.

Implementation of a new strategy to improve the peri-operative management of neuromuscular blockade and its effects on postoperative pulmonary complications.

Inappropriate dosing of neostigmine for antagonism of neuromuscular blockade has been associated with postoperative pulmonary complications. We evaluated the effects of a quality improvement initiative tailored to optimise the use of neostigmine in antagonising neuromuscular blockade on postoperative pulmonary complications, costs and duration of hospital stay. The quality improvement initiative consisted of: a reduction in available neostigmine aliquot sizes; a cognitive aid; an educational component; and a financial incentive for the intra-operative documentation of train-of-four measurement before administration of neostigmine. We conducted a pre-specified analysis of data obtained in our quality improvement study. Additional analyses were conducted in a propensity-matched cohort. An interrupted time series design was used to discriminate between the intervention and a counterfactual scenario. We analysed 12,025 consecutive surgical cases performed in 2015. Postoperative pulmonary complications occurred in 220 (7.5%) of 2937 cases pre-intervention and 568 (6.3%) of 9088 cases post-intervention. Adjusted regression analyses showed significantly a lower risk of postoperative pulmonary complications (OR 0.73 (95%CI 0.61-0.88); p = 0.001), lower costs (incidence rate ratio 0.95 (95%CI 0.93-0.97); p < 0.001) and shorter duration of hospital stay (incidence rate ratio 0.91 (95%CI 0.87-0.94); p < 0.001) after implementation of the quality improvement initiative. Analyses in a propensity-matched sample (n = 2936 per group) and interrupted time series analysis (n = 27,202 cases) confirmed the findings. Our data show that a local, multifaceted quality improvement initiative can enhance the quality of intra-operative neuromuscular blocking agent utilisation, thereby reducing the incidence of postoperative pulmonary complications.

Drugs for Dementia and Excess of Hospitalization: A Longitudinal French Study.

BACKGROUND: The impact of adverse effects of drugs for dementia on the risk of hospitalization has not been much studied despite the impact of hospitalizations on cognitive decline. OBJECTIVE: To determine if the main adverse effects of cholinesterase inhibitors and memantine may be associated with excess of hospitalization and to quantify the subsequent impact on healthcare expenditures. METHODS: A representative sample of the French national health insurance beneficiaries aged 65 and older and suffering from dementia were included and followed from 2007 to 2014. Binary logit models for longitudinal data (GEE estimation technique) were used to estimate the excess of hospitalization events related to the adverse effects of anti-dementia drugs and then to derive the additional costs of hospitalizations for the public health insurance fund. RESULTS: In total, 7,668 patients were followed, generating 111,133 individual observations over the 8-year period. Treated patients were hospitalized significantly more than non-treated patients (adjusted Odd Ratio (OR) = 1.08, 95% confidence interval (95% CI) = [1.02 to 1.13], p = 0.004), mainly with cholinesterase inhibitors for cardiac (OR = 1.21, 95% CI = [1.01 to 1.46], p = 0.034) and gastrointestinal events (OR = 1.43, 95% CI = [1.01-2.05], p = 0.045), especially with rivastigmine. When extrapolated to the entire population, this corresponded to an annual additional cost of € 55,000. CONCLUSION: Prescription of antidementia drugs, more specifically rivastigmine, increases the risk of hospitalizations via their cardiac and gastrointestinal adverse effects and lead to additional health care expenditures. Even though these results must be confirmed, they may encourage cautious consideration of the balance between benefits and harms before a prescription is given.

Adherence and Tolerability of Alzheimer's Disease Medications: A Pragmatic Randomized Trial.

BACKGROUND/OBJECTIVES: Post-marketing comparative trials describe medication use patterns in diverse, real-world populations. Our objective was to determine if differences in rates of adherence and tolerability exist among new users to acetylcholinesterase inhibitors (AChEI's). DESIGN: Pragmatic randomized, open label comparative trial of AChEI's currently available in the United States. SETTING: Four memory care practices within four healthcare systems in the greater Indianapolis area. PARTICIPANTS: Eligibility criteria included older adults with a diagnosis of possible or probable Alzheimer's disease (AD) who were initiating treatment with an AChEI. Participants were required to have a caregiver to complete assessments, access to a telephone, and be able to understand English. Exclusion criteria consisted of a prior severe adverse event from AChEIs. INTERVENTION: Participants were randomized to one of three AChEIs in a 1:1:1 ratio and followed for 18 weeks. MEASUREMENTS: Caregiver-reported adherence, defined as taking or not taking study medication, and caregiver-reported adverse events, defined as the presence of an adverse event. RESULTS: 196 participants were included with 74.0% female, 30.6% African Americans, and 72.9% who completed at least twelfth grade. Discontinuation rates after 18 weeks were 38.8% for donepezil, 53.0% for galantamine, and 58.7% for rivastigmine (P = .063) in the intent to treat analysis. Adverse events and cost explained 73.1% and 25.4% of discontinuation. No participants discontinued donepezil due to cost. Adverse events were reported by 81.2% of all participants; no between-group differences in total adverse events were statistically significant. CONCLUSIONS: This pragmatic comparative trial showed high rates of adverse events and cost-related non-adherence with AChEIs. Interventions improving adherence and persistence to AChEIs may improve AD management. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01362686 (https://clinicaltrials.gov/ct2/show/NCT01362686).

[Risk/benefit assessment in the treatment of Alzheimer's disease. Drug interactions]. / Valoración del riesgo/beneficio en el tratamiento de la enfermedad de Alzheimer. A propósito de una interacción.

INTRODUCTION: Anticholinergic drugs reduce the efficacy of acetylcholinesterase inhibitors (AChEI) and are inappropriate in elderly patients. The aim of this study is to determine the prevalence rate of prescription AChEI drugs and anticholinergics in a Healthcare Area, to identify the affected patients, and to inform the attending physicians, in order to evaluate the suitability of treatments. MATERIAL AND METHODS: A descriptive cross-sectional observational study of prevalence. Patients on treatment with AChEI and any anticholinergic drug in the first quarter of 2015 were selected. The review of Duran et al. was used as reference to identify anticholinergics, assigning a score to each drug according to its anticholinergic potency. Physicians were provided with a report about the interaction, the list of affected patients, and recommendations. RESULTS: A total of 486 patients were included in the study, representing 59.0% of total patients with Alzheimer's disease in the Area. There were 66.0% women, and 86.8% of the patients were older than 75 years, and with a mean of 9.2 drugs per patient. The mean number of anticholinergic drugs was 1.6, and 38.3% of patients were prescribed various anticholinergic drugs, with 23.9% on high potency anticholinergic drugs. A statistically significant association was found between taking an anticholinergic and AChEI concomitantly (P=.000; OR: 3.9). CONCLUSIONS: The prevalence of interactions between AChEI and anticholinergic drugs is relevant, considering that it affects vulnerable members of the population. Providing physicians with information about the interaction could help them make clinical decisions, and could improve patient safety, as well as health outcomes.

A Risk-Benefit Assessment of Dementia Medications: Systematic Review of the Evidence.

BACKGROUND: There is no cure for dementia, and no treatments exist to halt or reverse the course of the disease. Treatments are aimed at improving cognitive and functional outcomes. OBJECTIVE: Our objective was to review the basis of pharmacological treatments for dementia and to summarize the benefits and risks of dementia treatments. METHODS: We performed a systematic literature search of MEDLINE through November 2014, for English-language trials and observational studies on treatment of dementia and mild cognitive impairment. Additional references were identified by searching bibliographies of relevant publications. Whenever possible, pooled data from meta-analyses or systematic reviews were obtained. Studies were included for review if they were randomized trials or observational studies on dementia or mild cognitive impairment that evaluated efficacy outcomes or adverse outcomes associated with treatment. Studies were excluded if they evaluated non-FDA approved treatments, or if they evaluated treatment in disorders other than dementia and mild cognitive impairment. RESULTS: The literature search found 540 potentially relevant studies, of which 257 were included in the systematic review. In pooled trial data, cholinesterase inhibitors (ChEIs) produce small improvements in cognitive, functional, and global benefits in patients with mild to moderate Alzheimer's and Lewy body dementia, but the clinical significance of these effects are unclear. There is no significant benefit seen for vascular dementia. The efficacy of ChEI treatment appears to wane over time, with minimal benefit seen after 1 year. There is no evidence for benefit for those with advanced disease or those aged over 85 years. Adverse effects are significantly increased with ChEIs, in a dose-dependent manner. A two- to fivefold increased risk for gastrointestinal, neurological, and cardiovascular side effects is related to cholinergic stimulation, the most serious being weight loss, debility, and syncope. Those aged over 85 years have double the risk of adverse events compared with younger patients. Memantine monotherapy may provide some cognitive benefit for patients with moderate to severe Alzheimer's and vascular dementia, but the benefit is small and may wane over the course of several months. Memantine exhibits no significant benefit in mild dementia or Lewy body dementia or as an add-on treatment with ChEIs. Memantine has a relatively favorable side-effect profile, at least under controlled trial conditions. CONCLUSIONS: ChEIs produce small, short-lived improvements in cognitive function in mild to moderate dementia, which may not translate into clinically meaningful effects. Marginal benefits are seen with severe disease, long-term treatment, and advanced age. Cholinergic side effects, including weight loss, debility, and syncope, are clinically significant and could be especially detrimental in the frail elderly population, in which the risks of treatment outweigh the benefits. Memantine monotherapy may have minimal benefits in moderate to severe dementia, balanced by minimal adverse effects.

Antidementia drug use among community-dwelling individuals with Alzheimer's disease in Finland: a nationwide register-based study.

The objective of this study was to investigate the prevalence of acetylcholinesterase inhibitor (AChEI) and memantine use, duration of treatment, concomitant use of these drugs, and factors associated with the discontinuation of AChEI therapy during 2006-2009. We utilized data from a nationwide sample of community-dwelling individuals with a clinically verified Alzheimer's disease diagnosed during the year 2005 (n=6858) as a part of the MEDALZ-2005 study. During the 4-year follow-up, 84% used AChEI and 47% used memantine. Altogether, 22% of the sample used both drugs concomitantly. The median duration of the first AChEI use period was 860 (interquartile range 295-1458) days and 1103 (interquartile range 489-1487) days for the total duration of AChEI use. Although 20% of the AChEI users discontinued the use during the first year, over half of them restarted later. The risk of discontinuation was higher for rivastigmine [hazard ratio 1.34 (confidence interval 1.22-1.48)] and galantamine users [hazard ratio 1.23 (confidence interval 1.15-1.37)] compared with donepezil users in the adjusted model. In conclusion, median time for AChEI use was over 3 years and every fifth Alzheimer's disease patient used AChEI and memantine concomitantly during the follow-up. The low rate of discontinuation is consistent with the Finnish Care Guideline but in contrast to the results reported from many other countries.

Comparative cardiovascular safety of dementia medications: a cross-national study.

OBJECTIVES: To compare the cardiovascular safety of currently marketed dementia medications in new users in the United States and Denmark. DESIGN: Retrospective cohort study. SETTING: Nationally representative sample of Medicare beneficiaries from 2006 through 2009 and nationwide Danish administrative registries from 1997 through 2007. PARTICIPANTS: Individuals treated with a dementia medication aged 65 and older. MEASUREMENTS: Hospitalizations for myocardial infarction (MI), heart failure, and syncope or atrioventricular block in both cohorts; fatal or nonfatal MI and cardiac death in the Danish cohort; and all-cause mortality in sensitivity analyses. RESULTS: In 46,737 Medicare beneficiaries and 29,496 Danish participants, donepezil was the most frequently used medication. There were no substantial differences in the risk of MI or heart failure between participants using donepezil and those using other cholinesterase inhibitors (all hazard ratios (HR) crossing 1). In the Danish cohort, memantine was associated with fatal or nonfatal MI (HR = 1.33, 95% confidence interval (CI) = 1.08-1.63), cardiac death (HR = 1.31, 95% CI = 1.12-1.53), and a trend toward higher rates of hospitalization for MI (HR = 1.31, 95% CI = 0.98-1.76). Memantine was also associated with greater risk of all-cause mortality in the Medicare (HR = 1.20, 95% CI = 1.13-1.28) and Danish (HR = 1.83, 95% CI = 1.73-1.94) cohorts, suggesting that sicker individuals were selected for memantine therapy. CONCLUSION: Cholinesterase inhibitors have similar cardiovascular risk profiles. Associations between memantine and fatal outcomes in Denmark may be related, in part, to selection of sicker individuals for memantine therapy.

[Shortening of donepezil-induced QTc prolongation with a change in the interacting drug, after electrocardiograph monitoring by community pharmacists: a case report].

UNLABELLED: We used a mobile electrocardiograph to manage the adverse effects and interactions of drugs, especially QT-prolonging drugs, in a community pharmacy setting. We report the case of a patient in whom the risk of drug-induced torsades de pointes (TdP) was lowered, after monitoring by community pharmacists. CASE: An 80-year-old woman was under donepezil (5 mg/d) therapy for Alzheimer's disease and also taking other drugs that interact with donepezil, namely, benidipine (8 mg/d) and atorvastatin (10 mg/d). The patient was visited almost every month, and an electrocardiogram was usually obtained. QTc prolongation (avg. 470±9 ms) was observed in the first to third tests. Her doctor was informed about these results and the risk factors (advanced age, gender, and drugs interactions (benidipine and atorvastatin)) associated with TdP and asked to respond promptly since several cases of donepezil-induced TdP have been reported. As a result, benidipine was replaced with amlodipine, while the remaining drugs were continued. After the change, a significant decrease in QTc values were observed in the fourth to seventh tests (avg. 441±9 ms, p=0.010), thereby indicating a decrease in TdP risk. The Drug Interaction Probability Scale (object drug, donepezil; precipitant drug, benidipine) score was +6 (probable). Thus, QTc shortening was a result of differences in donepezil-benidipine and donepezil-amlodipine interactions.

Treatment of Alzheimer disease.

Alzheimer disease is the most common form of dementia, affecting nearly one-half [corrected] of Americans older than 85 years. It is characterized by progressive memory loss and cognitive decline. Amyloid plaque accumulation, neurofibrillary tau tangles, and depletion of acetylcholine are among the pathologic manifestations of Alzheimer disease. Although there are no proven modalities for preventing Alzheimer disease, hypertension treatment, omega-3 fatty acid supplementation, physical activity, and cognitive engagement demonstrate modest potential. Acetylcholinesterase inhibitors are first-line medications for the treatment of Alzheimer disease, and are associated with mild improvements in cognitive function, behavior, and activities of daily living; however, the clinical relevance of these effects is unclear. The most common adverse effects of acetylcholinesterase inhibitors are nausea, vomiting, diarrhea, dizziness, confusion, and cardiac arrhythmias. Short-term use of the N-methyl-D-aspartate receptor antagonist memantine can modestly improve measures of cognition, behavior, and activities of daily living in patients with moderate to severe Alzheimer disease. Memantine can also be used in combination with acetylcholinesterase inhibitors. Memantine is generally well tolerated, but whether its benefits produce clinically meaningful improvement is controversial. Although N-methyl-D-aspartate receptor antagonists and acetylcholinesterase inhibitors can slow the progression of Alzheimer disease, no pharmacologic agents can reverse the progression. Atypical antipsychotics can improve some behavioral symptoms, but have been associated with increased mortality rates in older patients with dementia. There is conflicting evidence about the benefit of selegiline, testosterone, and ginkgo for the treatment of Alzheimer disease. There is no evidence supporting the beneficial effects of vitamin E, estrogen, or nonsteroidal anti-inflammatory drug therapy.

How do we treat people with dementia in Croatia.

The current clinical view on pharmacological treatment and the Croatian reality regarding approved antidementia drugs is presented. Dementia is a syndrome of high incidence and Alzheimer's disease is the most common cause of dementia. New data show that dementia prevalence will nearly double every 20 years, and we believe that current estimated number of persons with dementia (PWD) for Croatia is more than 80,000. The standard treatment with antidementia drugs is unavailable in Croatia, for the majority of PWD, because antidementia drugs are not on the reimbursement list, although Croatian algorithm for psychopharmacological treatment and Alzheimer Disease Societies Croatia recommend early and adequate treatment. Alzheimer's dementia is becoming a world's health priority in 21st century, so we strongly believe that antidementia drugs should be reimbursed in Croatia.