Cholinesterase Inhibitors Discontinuation Research Articles

Antidementia Medication Use in Nursing Home Residents.

Antidementia medication can provide symptomatic improvements in patients with Alzheimer's disease, but there is a lack of consensus guidance on when to start and stop treatment in the nursing home setting. We describe utilization patterns of cholinesterase inhibitors (ChEI) and memantine for 3,50,197 newly admitted NH residents with dementia between 2011 and 2018. Overall, pre-admission use of antidementia medications declined from 2011 to 2018 (ChEIs: 44.5% to 36.9%; memantine: 27.4% to 23.2%). Older age, use of a feeding tube, and greater functional dependency were associated with lower odds of ChEI initiation. Coronary artery disease, parenteral nutrition, severe aggressive behaviors, severe cognitive impairment, and high functional dependency were associated with discontinuation of ChEIs. Comparison of clinical factors related to anti-dementia drug treatment changes from pre to post NH admission in 2011 and 2018 revealed a change toward lower likelihood of initiation of treatment among residents with more functional dependency and those with indicators of more complex illness as well as a change toward higher likelihood of discontinuation in residents having 2 or more hospital stays. These prescribing trends highlight the need for additional research on the effects of initiating and discontinuing antidementia medications in the NH to provide clear guidance for clinicians when making treatment decisions for individual residents.

Scoping Review of Randomized Trials With Discontinuation of Medicines in Older Adults.

To map the randomized trial evidence describing the feasibility of discontinuing active medications with potential adverse effects in older patients. Scoping review with systematic search of PubMed, Embase, and Cochrane Library. Randomized trials investigating discontinuation of a single medicine or medicine class in patients with mean age ≥65years. We extracted trial characteristics including study design and assessed bias. As proxies for the "feasibility of discontinuation," we extracted the "dropout rate" and "disease recurrence rate." We identified 40 trials investigating discontinuation of symptomatic (n= 26), preventive (n= 6), or both preventive and symptomatic medicines (n= 8) against psychiatric (n= 10), neurologic (n= 9), musculoskeletal (n= 8), cardiovascular (n= 5), respiratory (n= 4), and urologic diseases (n= 4). Five discontinuation designs were used, 75% (30/40) of trials were placebo-controlled, and 48% (19/40) of trials had bias disfavoring discontinuation. The dropout rate was similar between the discontinuation group and the continuation group in 79% of the trials (30/38), whereas disease recurrence was similar in 72% (23/32) of the trials. In 42% (13/31) of trials reporting both dropout rate and disease recurrence rate, the differences between groups were statistically insignificant and less than 10%; these trials investigated discontinuation of cholinesterase inhibitors for Alzheimer's disease in various settings (n= 3), alendronate for osteoporosis (n= 3), glucosamine for osteoarthritis, lithium as adjunct for unipolar depression, statins for cardiovascular disease in patients with limited life expectancy, droxidopa for neurogenic orthostatic hypotension, tamsulosin for lower urinary tract symptoms, sertraline for major depressive episode, and fentanyl patch for low back or osteoarthritis pain. We identified 40 randomized trials using a variety of designs investigating discontinuation of both symptomatic and preventive medicines in older patients. Discontinuation of medicines seems feasible for most of the investigated medicines. This scoping review can guide clinical practice and future trials on deprescribing.

Anticholinergic co-prescribing in nursing home residents using cholinesterase inhibitors: Potential deprescribing cascade.

Polypharmacy may result from inappropriate prescribing of medications to treat adverse drug reactions (ADRs), i.e., "prescribing cascade." A potentially harmful prescribing cascade affecting those with severe dementia can result when anticholinergics are prescribed to manage side effects of cholinesterase inhibitors (ChEIs). We investigated 1) factors associated with co-prescribing of anticholinergics and ChEIs and 2) whether discontinuation of ChEIs was associated with subsequent discontinuation of anticholinergics-a potentially beneficial reversal or "deprescribing cascade." We conducted a retrospective analysis of linked Medicare Part A/B/D claims, Master Beneficiary Summary File, Minimum Data Set, Area Health Resource File, and Nursing Home Compare from 2015 to 2016. Subjects were Medicare beneficiaries residing in nursing homes, ≥65 years old with severe dementia admitted for non-skilled stays, who were prescribed ChEIs. Cross-sectional analysis evaluated factors associated with co-prescribing of anticholinergics with ChEIs. Longitudinal Cox proportional hazards regression examined whether discontinuation of ChEIs was associated with subsequent discontinuation of anticholinergics over a 1-year period. We found 15% of our sample experienced co-prescribing of anticholinergics and ChEIs. Several resident and facility-level factors were associated with co-prescribing anticholinergics. Advancing age, minority race or ethnicity, end-stage renal disease, heart failure, and poor appetite were associated with a decreased likelihood of co-prescribing. Female sex, polypharmacy, and non-geriatric prescriber-type were associated with a higher likelihood of co-prescribing. In longitudinal analyses, we observed that discontinuation of ChEIs was associated with a reduced likelihood (HR 0.58 [95% CI, 0.47-0.71]) of discontinuing any medications with anticholinergic properties, except for bladder antimuscarinics (HR 1.32 [95% CI, 0.83-2.09]). Younger, healthier older adults with dementia were more likely to experience co-prescribing anticholinergics and ChEIs. Discontinuation of anticholinergics was infrequent. Further research is needed to understand prescribers' ability to recognize and reverse potential prescribing cascades through deprescribing.

Rituximab in Myasthenia Gravis- Experience from a Low- and Middle-Income Country (LMIC) Setting.

Myasthenia gravis (MG) is an immune-mediated disorder of the neuromuscular junction. About 10% are refractory to immunosuppressive therapy. To analyze the response of patients with generalized MG to rituximab. A retrospective review of patients with MG who received rituximab was carried out (n = 13, M:F = 6:7, mean age: 44.84 ± 15.73 years). Myasthenia Gravis Foundation of America (MGFA), MGFA post-intervention status (MGFA-PIS), and Myasthenia Gravis Status and Treatment Intensity (MGSTI) were assessed before and after rituximab. The duration of MG was 104.07 ± 92.25 months. Before rituximab, the MGFA was IIA/IIB/IIIA/IIIB/IVB/V in 1/1/2/6/2/1 patients and MGSTI was four in eight patients and six in three patients. The mean duration of follow up was 20.92 ± 14.06 months (range, 4 to 42 months). Dose reduction or discontinuation of cholinesterase inhibitors could be achieved 12 patients. Complete stable remission (CSR) and pharmacologic remission (PR) were achieved in one and four patients respectively and five patients had minimal manifestations. Most patients attained level 0, 1 or 2 MGSTI at last follow up. No rituximab infusion-related adverse events were noted. Three patients had exacerbation of MG between one to five weeks after rituximab administration. Three patients died, one each due to a cardiac event unrelated to MG or treatment, complications related to myasthenic crisis, and coronavirus disease. Rituximab was effective in bringing about remission in MG and can be considered as a first-line agent. However, it has to be administered under close supervision as some patients develop exacerbation of MG akin to steroid-induced worsening.

Drug cost optimization of cholinesterase inhibitor therapy in advanced dementia: Results of a prospective study of discontinuation

Purpose: To investigate the effect of discontinuing treatment with cholinesterase inhibitors (ChEIs) on drug costs in patients with advanced dementia.
 Methods: Severe dementia patients receiving ChEI treatment for over 12 months (n = 43) aged over 65 years (mean age = 82.6 ± 7.5 years) were recruited from 8 nursing homes located in Alicante, Spain. ChEI treatment was discontinued in 23 patients. Here, we report the results from a cost-minimization analysis to evaluate the drug costs with a follow-up period of three months. The drug costs were prospectively analyzed based on drug acquisition costs.
 Results: At the end of the follow-up, the mean monthly drug costs were €52.68 ± 22.48 in the discontinuation group and €122.54 ± 44.74 in the continuation group - a significant difference of means of -€69.86 (95 % CI, -91.24 to -48.48; p = 0.000). The monthly drug cost reduction for the ChEI discontinuation group was €1,533.35.
 Conclusion: ChEI discontinuation appears to be a possible option for minimizing treatment costs in institutionalized patients with advanced dementia.

Cholinesterase Inhibitor Use in Patients With Dementia Admitted to a Palliative Care Unit.

Current guidelines suggest that patients with severe dementia on cholinesterase inhibitors (CHEIs) should discontinue their CHEIs by taper. This study aims to define the prevalence of patients admitted to a palliative care unit (PCU) with dementia on a CHEI and to determine whether these patients were tapered off their CHEIs according to current deprescribing guidelines. This is a descriptive retrospective chart review that examined patients admitted to a PCU with dementia on a CHEI from January 2015 to June 2019. Individuals admitted to the PCU with a primary or comorbid diagnosis of dementia were identified. Their corresponding CHEI dose, frequency and discontinuation pattern were identified. Data were analyzed using descriptive statistics. A total of 36 patients were admitted to the PCU with dementia on a CHEI (prevalence of 2.3%). The median length of stay was 21 days. For 31 of these patients, their CHEI was discontinued, only 9 of which had a taper. Of the 24 patients who discontinued their CHEI suddenly, 10 patients had an order to discontinue their CHEI in the last 2 days before their date of death. This study suggests that although patients admitted to a PCU with dementia have their CHEI discontinued, the discontinuation was done without a taper. In many cases the CHEIs were continued through the active stage of dying. Future work should explore reasons why PCU physicians are mostly late to taper CHEIs for patients admitted with dementia.

Fall-Related Hospitalizations in Nursing Home Residents Co-Prescribed a Cholinesterase Inhibitor and Beta-Blocker.

To examine the association between hospitalization for a fall-related injury and the co-prescription of a cholinesterase inhibitor (ChEI) among persons with dementia receiving a beta-blocker, and whether this potential drug-drug interaction is modified by frailty. Nested case-control study using population-based administrative databases. All nursing homes in Ontario, Canada. Persons with dementia aged 66 and older who received at least one beta-blocker between April 2013 and March 2018 following nursing home admission (n = 19,060). Cases were persons with dementia with a hospitalization (emergency department visit or acute care admission) for a fall-related injury with concurrent beta-blocker use. Each case (n = 3,038) was matched 1:1 to a control by age (±1 year), sex, cohort entry year, frailty, and history of fall-related injuries. The association between fall-related injury and exposure to a ChEI in the 90 days prior was examined using multivariable conditional logistic regression. Secondary exposures included ChEI type, daily dose, incident versus prevalent use, and use in the prior 30 days. Subgroup analyses considered frailty, age group, sex, and history of hospitalization for fall-related injuries. Exposure to a ChEI in the prior 90 days occurred among 947 (31.2%) cases and 940 (30.9%) controls. In multivariable models, no association was found between hospitalization for a fall-related injury and prior exposure to a ChEI in persons with dementia dispensed beta-blockers (adjusted odds ratio = .96, 95% confidence interval = .85-1.08). Findings were consistent across secondary exposures and subgroup analyses. Among nursing home residents with dementia receiving beta-blockers, co-prescription of a ChEI was not associated with an increased risk of hospitalization for a fall-related injury. However, we did not assess for its association with falls not leading to hospitalization. This finding could inform clinical guidelines and shared decision making between persons with dementia, caregivers, and clinicians concerning ChEI initiation and/or discontinuation.

OUTCOMES OF DISCONTINUING CHOLINESTERASE INHIBITORS IN NURSING HOME RESIDENTS WITH SEVERE DEMENTIA

Some clinical guidelines advocate for the withdrawal of cholinesterase inhibitors (ChEIs) in patients with severe dementia. However, there have been no studies of the outcomes of deprescribing ChEIs specifically in patients with severe dementia, and concerns about subsequent worsening of behavioral symptoms may serve as a barrier to ChEI discontinuation. Our objective was to evaluate the impact of deprescribing ChEIs on aggressive behaviors and depression severity in older nursing home (NH) residents with severe dementia. We conducted a retrospective cohort study using Medicare claims, Part D prescriptions, Minimum Data Set (MDS) v3.0, Area Health Resource File, and Nursing Home Compare, for non-skilled NH residents aged 65+ with severe dementia receiving AChEIs with ≥2 MDS assessments in 2016 (n=30,788). The Aggressive Behavior Scale (ABS) and the Patient Health Questionnaire (PHQ-9) evaluated aggression and depression, respectively. Marginal structural models with inverse probability of treatment weights evaluated the association of deprescribing with outcomes, accounting for time-dependent confounding. The sample was primarily white (78.7%), female (76.6%), >80 years old (77.6%), and 22.8% were deprescribed ChEIs. In adjusted models, deprescribing was not associated with aggression (0.002 point increase in ABS, p=0.90) or depression (0.04 point increase in PHQ-9, p=0.50). Deprescribing ChEIs in NH residents with severe dementia did not lead to an increase in aggressive behaviors or depression severity. Our findings provide insight into the potential risks and benefits associated with deprescribing ChEIs and help inform decision-making in patients with severe dementia.

Predictors of Cholinesterase Discontinuation during the First Year after Nursing Home Admission

ObjectivesFor persons with dementia, the appropriate duration of cholinesterase inhibitor (ChEI) use remains unclear. We examined patterns of ChEI use during nursing home (NH) transition and the factors associated with discontinuation following admission. DesignPopulation-based retrospective cohort study using linked health administrative and Resident Assessment Instrument Minimum Dataset, version 2.0 databases. Setting and participantsA total of 47,851 older adults (mean age = 84.8 years, standard deviation = 6.8) with dementia newly admitted to a NH in Ontario, Canada between 2011 and 2015. MeasurementsChEI use at admission and during the following year was identified from prescription claims. Resident sociodemographic and health characteristics at admission, including a 72-item frailty index, were derived from the Resident Assessment Instrument Minimum Dataset 2.0. Additional resident and prescriber characteristics were derived from administrative data. Discontinuation was defined as a 30+-day gap in ChEI supply. Multivariable subdistribution hazard models were used to estimate the independent effect of resident frailty and other factors on ChEI discontinuation. ResultsApproximately one-third (17,560) of residents with dementia were on a ChEI at admission. Among this group, 17.7% (3110) discontinued use over follow-up. Incidence of discontinuation was significantly higher among residents with syncope [subdistribution hazard ratio, sHR = 2.21, 95% confidence interval, CI (1.52, 3.22)], more severe behavioral symptoms [sHR = 1.79, 95% CI (1.57, 2.05)], cognitive impairment [sHR = 1.26, 95% CI (1.07, 1.48)], higher frailty, [sHR = 1.19, 95% CI (1.04, 1.36)], and a primary prescriber active in the NH [sHR = 1.28, 95% CI (1.14, 1.45)]. A significantly lower incidence was observed for older and unmarried residents and those with a longer duration of use. Conclusions/ImplicationsLess than one-fifth of residents on a ChEI at admission discontinued use during the following year. Although some of the predictors of discontinuation align with past research and current clinical recommendations, others were unexpected and point to novel drivers of ChEI use. Future investigations should explore the varied reasons underlying these associations and resident outcomes associated with ChEI discontinuation.

Pharmacological interventions for apathy in Alzheimer's disease.

Despite the high prevalence of apathy in Alzheimer's disease (AD), and its harmful effects, there are currently no therapies proven to treat this symptom. Recently, a number of pharmacological therapies have been investigated as potential treatments for apathy in AD. Objective 1: To assess the safety and efficacy of pharmacotherapies for the treatment of apathy in Alzheimer's disease (AD).Objective 2: To assess the effect on apathy of pharmacotherapies investigated for other primary outcomes in the treatment of AD. We searched the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (ALOIS), MEDLINE, Embase, CINAHL, PsycINFO, LILACS, ClinicalTrials.gov and the World Health Organization (WHO) portal, ICTRP on 17 May 2017. Eligible studies were double-blind, randomized, placebo-controlled trials (RCTs) investigating apathy as a primary or secondary outcome in people with AD. Three review authors extracted data. We assessed the risks of bias of included studies using Cochrane methods, and the overall quality of evidence for each outcome using GRADE methods. We calculated mean difference (MD), standardized mean difference (SMD) or risk ratio (RR) with 95% confidence intervals on an intention-to-treat basis for all relevant outcome measures. We included 21 studies involving a total of 6384 participants in the quantitative analyses. Risk of bias is very low to moderate. All studies reported appropriate methods of randomization and blinding. Most studies reported appropriate methods of allocation concealment. Four studies, three with methylphenidate and one with modafinil, had a primary aim of improving apathy. In these studies, all participants had clinically significant apathy at baseline. Methylphenidate may improve apathy compared to placebo. This finding was present when apathy was assessed using the apathy evaluation scale (AES), which was used by all three studies investigating methylphenidate: MD -4.99, 95% CI -9.55 to -0.43, n = 145, 3 studies, low quality of evidence, but not when assessed with the neuropsychiatric inventory (NPI)-apathy subscale, which was used by two of the three studies investigating methylphenidate: MD -0.08, 95% CI -3.85 to 3.69, n = 85, 2 studies, low quality of evidence. As well as having potential benefits for apathy, methylphenidate probably also slightly improves cognition (MD 1.98, 95% CI 1.06 to 2.91, n = 145, 3 studies, moderate quality of evidence), and probably improves instrumental activities of daily living (MD 2.30, 95% CI 0.74 to 3.86, P = 0.004, n = 60, 1 study, moderate quality of evidence), compared to placebo. There may be no difference between methylphenidate and placebo in the risk of developing an adverse event: RR 1.28, 95% CI 0.67 to 2.42, n = 145, 3 studies, low quality of evidence. There was insufficient evidence from one very small study of modafinil to determine the effect of modafinil on apathy assessed with the FrSBe-apathy subscale: MD 0.27, 95% CI -3.51 to 4.05, n = 22, 1 study, low quality of evidence. In all other included studies, apathy was a secondary outcome and participants were not selected on the basis of clinically significant apathy at baseline. We considered the evidence on apathy from these studies to be indirect and associated with publication bias. There was low or very low quality of evidence on cholinesterase inhibitors (ChEIs) (six studies), ChEI discontinuation (one study), antipsychotics (two studies), antipsychotic discontinuation (one study), antidepressants (two studies), mibampator (one study), valproate (three studies) and semagacestat (one study). Methylphenidate may demonstrate a benefit for apathy and may have slight benefits for cognition and functional performance in people with AD, but this finding is associated with low-quality evidence. Our meta-analysis is limited by the small number of studies within each drug class, risk of bias, publication bias, imprecision and inconsistency between studies. Additional studies should be encouraged targeting people with AD with clinically significant apathy which investigate apathy as a primary outcome measure, and which have a longer duration and a larger sample size. This could increase the quality of evidence for methylphenidate, and may confirm whether or not it is an effective pharmacotherapy for apathy in AD.

Poster Number: EI 19 - A Review of Cholinesterase Inhibitor Discontinuation in Alzheimer's Disease: Should Clinicians Ever Stop Treatment?

Poster Number: EI 19 - A Review of Cholinesterase Inhibitor Discontinuation in Alzheimer's Disease: Should Clinicians Ever Stop Treatment?

Withdrawal of Antidementia Drugs in Older People: Who, When and How?

The evidence base to guide withdrawal of antidementia medications in older people with dementia is limited; while some randomised controlled studies have considered discontinuation of cholinesterase inhibitors (ChEIs), no such studies examining discontinuation of the N-methyl-D-aspartate receptor antagonist memantine have been conducted to date. The purpose of this opinion article was to summarise the existing evidence on withdrawal of cholinesterase inhibitors and memantine, to highlight the key considerations for clinicians when making these prescribing decisions and to offer guidance as to when and how treatment might be discontinued. Until the evidence base is enhanced by the findings of large-scale, randomised controlled discontinuation trials of ChEIs and memantine that use multiple, clinically relevant, cognitive, functional and behavioural outcome measures, clinicians' prescribing decisions involve balancing the risks of discontinuation with side effects and costs of continued treatment. Such decisions must be highly individualised and patient-centred.

Cholinesterase inhibitor discontinuation in patients with Alzheimer's disease: a meta-analysis of randomized controlled trials.

This meta-analysis examined the effects of cholinesterase inhibitor (ChEI) discontinuation in patients with Alzheimer's disease (AD). Electronic records up to March 2014 were searched from MEDLINE, Embase, PsycINFO, Cochrane Library, Allied and Complementary Medicine Database, and Cumulative Index to Nursing and Allied Health Literature. Search terms included Alzheimer's disease and cholinesterase inhibitors, plus discontinuation or cessation or tapering or withdrawal. There were no language limits. Randomized, double-blind, placebo-controlled studies investigating the effect of ChEI discontinuation on patients with AD according to standardized criteria (eg, National Institute of Neurologic and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association, DSM-IV) and presenting measurable results of neuropsychological testing were included. Demographics, setting, ChEI treatment length, discontinuation protocol, follow-up duration, study outcomes, and dropouts during the double-blind phase were extracted. Of 1,430 records returned, 18 were reviewed. Five ChEI discontinuation randomized controlled trials (N = 321 continued and N = 332 discontinued, following patients for 1.5-24 months) were analyzed. Discontinued patients demonstrated a significant worsening of cognition (standard mean Mini-Mental State Examination difference: -0.29 [95% CI, -0.45 to -0.13], N = 300 continued/307 discontinued, P < .001), a significant worsening of neuropsychiatric symptoms (standard mean Neuropsychiatric Inventory difference: -0.32 [-0.51 to -0.12], N = 199/211, P = .001), and significantly higher dropout rates (risk ratio [RR] = 1.33 [1.11-1.59], N = 321/332, P = .002) compared to those who continued. No difference in adverse events was observed (RR = 1.01 [0.85-1.20], N = 314/326, P = .92). ChEI discontinuation may have negative effects on cognition and neuropsychiatric symptoms, a finding corroborated by a higher incidence of trial dropout.

Predictors of worsening following cholinesterase inhibitor discontinuation trial in institutionalized persons with moderate to severe Alzheimer's disease: Results of a double-blind, placebo controlled trial

Predictors of worsening following cholinesterase inhibitor discontinuation trial in institutionalized persons with moderate to severe Alzheimer's disease: Results of a double-blind, placebo controlled trial

Cholinesterase Inhibitor Discontinuation in Institutionalized Persons with Moderate to Severe AD: Results of a Double-Blind, Placebo Controlled Trial

Cholinesterase Inhibitor Discontinuation in Institutionalized Persons with Moderate to Severe AD: Results of a Double-Blind, Placebo Controlled Trial

A 2-Year Prospective Cohort Study of Antidementia Drug Non-Persistency in Mild-to-Moderate Alzheimer's Disease in Europe

There is no consensus on when and how to discontinue cholinesterase inhibitors (ChEI). Predictors of non-persistency of antidementia drugs have been poorly investigated, mostly during short-term periods and using administrative data. The aim of this study was to investigate the incidence and predictors of ChEI switch and discontinuation among subjects with ascertained Alzheimer's disease (AD). A total of 557 community-dwelling, mild-to-moderate AD subjects initiating ChEIs in 29 European clinic centres were assessed twice-yearly for 2 years. Antidementia drug exposure was recorded through a physician-administered structured questionnaire to document any change in drug therapy (start and stop dates, reasons). Discontinuation was defined as >35 days without any antidementia drug. Switch was defined as a change for any antidementia drug strategy within 35 days after ChEI cessation. Two separate time-dependent multivariate Cox survival analyses were conducted to identify predictors of discontinuation and switch. The incidences of discontinuation and switch were 9.65 and 12.47/100 person-years, respectively. Behavioural disturbances, low body mass index, falls, decline in Mini-Mental State Examination (MMSE) score, and AD-related hospitalization predicted discontinuation. MMSE score, decline in activities of daily living score, aberrant motor behaviour, shorter AD duration and higher nurse resource use predicted a switch. An ineffective ChEI dose and clinic specialty predicted both outcomes. Sensitivity analyses using a 60-day cut-off provided stable results. Several predictors were identified: adverse drug events and their predisposing factors, perceived loss of efficacy or disease progression on cognitive or functional scales, behavioural disturbances, hospitalization and professional practices. The latter implies a need for harmonization in AD drug prescription practice.

Less Education Predicts Anticholinesterase Discontinuation in Dementia Patients

We investigated patient socio-demographic, clinical and functional factors predicting cholinesterase inhibitor discontinuation by patients presenting to a memory clinic in Saskatoon, Saskatchewan. Data collection began in March 2004 at the Rural and Remote Memory Clinic where family physicians referred their non-institutionalized patients. Neurological and neuropsychological assessment, patient and caregiver questionnaires provided the socio-demographic, clinical and functional variables. Univariate logistic regression analysis was used to examine possible associations between each independent variable and the binary outcome variable of treatment discontinuation. Multivariate logistic regression was used to determine predictors of cholinesterase inhibitor discontinuation within six months of drug initiation. Our sample consisted of the first 63 patients (60.3% female) for whom we prescribed a cholinesterase inhibitor. The mean age at clinic day was 74.56 years (SD=7.78). We found that years of formal education was the only variable significantly associated with cholinesterase inhibitor discontinuation by six months. The more years of formal education, the lower the rate of drug discontinuation by six months. Likelihood of cholinesterase inhibitor discontinuation by six months was predicted by fewer years of formal education.

Discontinuing cholinesterase inhibitors: results of a survey of Canadian dementia experts

Cholinesterase inhibitors (ChEIs) are being used for increasingly long periods of time, even in patients with severe Alzheimer's disease. Because there is little data to help clinicians to decide on when it is safe and appropriate to discontinue ChEIs after long-term use, practices may vary widely. An internet-based survey was undertaken of Canadian dementia experts (geriatric psychiatrists, neurologists, geriatricians) involved in clinical trial research. Recommendations for ChEI discontinuation were determined based on responses to questions dealing with patient/caregiver preference, administrative considerations, effectiveness, and adverse events. There was reasonable consensus that ChEIs should be discontinued based on patient and caregiver preference, and in the presence of severe bothersome adverse events. There was much less consensus on issues related to effectiveness - in particular, what constitutes greater than expected decline. There was a general reluctance to rely on any single measure of cognition, function and/or behavior, and in particular, the MMSE was seen as unhelpful for making decisions about discontinuation. Recommendations for discontinuing ChEIs after long-term use from a survey of dementia experts are presented. Ideally, clinical practice guidelines based on controlled discontinuation trials are needed.

Discontinuation of Cholinesterase Inhibitor Treatment and Determinants thereof in the Netherlands

The cholinesterase inhibitors (ChEIs) rivastigmine and galantamine have been approved for the treatment of mild to moderate Alzheimer's disease in the Netherlands. Differences between ChEIs regarding persistence or the use of effective doses in daily clinical practice have been observed. However, most studies assessing ChEI discontinuation and associated determinants have been conducted in North America and there is a lack of knowledge about ChEI discontinuation and its determinants in daily clinical practice in Europe. To assess ChEI discontinuation in daily practice in the Netherlands and to seek its determinants, including suboptimal utilization. A retrospective cohort study was performed using data from the Dutch PHARMO Record Linkage System. Included patients were aged > or =50 years at first dispensing of a ChEI, had a first dispensing of a ChEI between 1998 and 2008, had a prior medication history of 12 months and had at least one subsequent dispensing of any kind of medication. The proportion of patients who discontinued ChEIs over 3 years was determined. Cox regression was used to assess determinants for early (< or =6 months) discontinuation and, separately, for late discontinuation during a subsequent 30-month follow-up among those persisting with treatment for >6 months. At 6 months, 30.8% of 3369 study patients had discontinued ChEIs, compared with 59.0% after 3 years. Thirty-five percent of patients taking rivastigmine reached the WHO-defined daily dose compared with 80% taking galantamine. At 6 months, compared with regular-dose rivastigmine, low-dose rivastigmine or low-dose galantamine was associated with an increased risk of early discontinuation, whereas regular-dose galantamine was associated with a decreased risk, as was concurrent use of cardiac medications, drugs for Parkinson's disease, propulsives, selective serotonin reuptake inhibitors and benzodiazepines. Associations of ChEI type/dose or co-medications with discontinuation among patients persisting for > 6 months differed somewhat from associations with discontinuation before 6 months. Fewer patients taking rivastigmine than those taking galantamine reached recommended doses. Furthermore, patients taking rivastigmine had an increased risk of early discontinuation compared with patients taking galantamine. Adverse effects leading to treatment intolerance and suboptimal utilization may have been contributing factors to these observed differences.

Predictive Factors of Discontinuation and Switch of Cholinesterase Inhibitors in Community-Dwelling Patients with Alzheimerʼs Disease

The efficacy of cholinesterase inhibitors (ChEIs), especially over the long term, is still under discussion. There is a lack of data concerning the optimal drug treatment duration and the reasons for discontinuation, particularly outside the clinical trial setting. To identify predictive factors of discontinuation and switch of ChEIs in a real-world setting. A multicentre cohort study of 686 patients with mild-to-moderate ambulatory Alzheimer's disease who were diagnosed in 16 Alzheimer's disease expert centres in 2000-2 and who were assessed twice yearly for 2 years. The main outcome measure was ChEI discontinuation and switch (analysed using Cox survival analyses). After 2 years, of the 611 subjects treated with a ChEI at baseline, 100 subjects had switched or discontinued ChEI therapy (incidence rate 12.7 [95% CI 10.2, 15.2] per 100 person-years). The incidences of switching and discontinuation were 9.2 (95% CI 7.0, 11.3) and 3.6 (95% CI 2.3, 4.8) per 100 person-years, respectively. In the multivariate analysis, predictive factors for switching were an ineffective ChEI dose (adjusted hazard ratio [HR(a)] = 6.91, 95% CI 3.08, 15.49), rapid cognitive decline (HR(a) = 4.10, 95% CI 1.85, 9.05), hospitalization unrelated to Alzheimer's disease (HR(a) = 2.33, 95% CI 1.07, 5.09) and anxiety (HR(a) = 2.08, 95% CI 1.16, 3.73). Predictive factors of discontinuation were: hospitalization related (HR(a) = 9.14, 95% CI 2.69, 31.07) or unrelated (HR(a) = 4.23, 95% CI 1.54, 11.59) to Alzheimer's disease, use of an anticholinergic drug (HR(a) = 4.26, 95% CI 1.46, 12.45) and weight loss (HR(a) = 3.77, 95% CI 1.15, 12.33). This study highlights four types of predictors of switch or discontinuation, reflecting disease progression, reconsideration of ChEI benefits, adverse drug reactions to ChEIs and inappropriate concurrent use of anticholinergic drugs. Attention should be paid to anticholinergic agents and prescribers should be given better information about these drugs.