Use of Cholinesterase Inhibitors Plus Memantine in Long-Term Care: A Resident Assessment Instrument Study

A diagnosis of Alzheimer’s disease is common in long-term care settings, and current treatment options typically include either a cholinesterase inhibitor or memantine. The authors conducted a pilot study that included patients residing in a Finnish nursing home to assess the use of these agents alone and in combination. The Resident Assessment Instrument (RAI), a comprehensive, validated assessment tool was used to measure changes in the participants’ clinical condition and in outcomes, such as cognitive decline, depression, and social engagement. The authors found that combination therapy with a cholinesterase inhibitor and memantine was associated with favorable  outcomes, with patients receiving combination therapy having less deterioration in cognition and communication skills and requiring fewer restrictions. In addition, more study participants receiving dementia medication were able to discontinue using antipsychotics. To put their study findings in context, the authors provide a brief review of the literature.
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Alzheimer’s disease, the most common form of dementia, is a major factor leading to long-term care (LTC) placement. The current pharmacologic options for treating Alzheimer’s disease are donepezil, galantamine, and rivastigmine, which are cholinesterase inhibitors (CIs), and
memantine, which is an N-methyl-D-aspartate receptor antagonist. In studies of patients with severe Alzheimer’s disease, donepezil has been found to preserve function and cognition, and galantamine and rivastigmine have been found to improve cognition.^1-3 Memantine treatment has been shown to reduce care dependence among patients with severe dementia.⁴ In a randomized controlled trial, combining memantine with donepezil to treat moderate to severe Alzheimer’s disease resulted in improved measures of cognition, activities of daily living (ADLs), and behavior.⁵ Two more recent observational, long-term, real-life studies have demonstrated positive effects for the concomitant use of CI drugs and memantine for patients living at home.^6,7 In one of these studies, which included 943 patients with probable Alzheimer’s disease, time to nursing home admission was significantly extended by adding memantine to CI treatment.⁶ In the other study, which included data comprising 955 patient-years, this combination therapy slowed cognitive and functional decline, with the clinical benefit sustained for at least 2 years.⁷

In Western countries, about 75% of LTC residents have a dementia diagnosis.^8-10 Several studies have shown that concomitant use of CI drugs and memantine is safe for this population,^1,2,4,11,12 and this combination is often used among persons with end-stage dementia.^13,14 Still, less than half of patients with dementia receive medication for the condition in LTC facilities or upon admission to a nursing home or hospice care.^13,15-18 In the months following admission to such facilities, medication is discontinued in about half of residents, depending on the severity of the dementia.^18,19 However, the average time of CI use has been reported to last from 9 months to more than 2 years.^17,20 In a retrospective study by a CI review committee in an LTC facility, one-third of CI users had recommendations to discontinue these agents because of insufficient benefit and most did so.²¹

In light of these data, we sought to determine whether the use of a CI plus memantine would have similar positive results in our nursing home, the Koukkuniemi Home for the Elderly, which is located in Tampere, Finland. We reviewed the literature further and conducted a pilot study using data from the Resident Assessment Instrument (RAI), a validated assessment tool that we have used in our nursing home since 2001.

Literature Review on Agents Used for Severe Dementia

Both CI agents and memantine have been associated with improved cognition and function in LTC residents with severe dementia. Donepezil had positive trends on the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Inventory (ADCS–ADL) at 6 months’ treatment and was associated with less decline on 11 of 13 ADCS–ADL items that are used to score disease severity.^11,22 In other studies with donepezil, cognition improved over a 6-month period, as measured by several tools, including the Severe Impairment Battery examination, the Mini-Mental State Examination (MMSE), and the Clinician’s Interview-Based Impression of Change–Plus Carer Interview.^1,11,22-24 In a study assessing the safety and efficacy of galantamine, cognition was significantly improved in nursing home residents with severe Alzheimer’s disease who were taking this agent, compared with those receiving a placebo.² In a rivastigmine study, no decline in MMSE scores was revealed over 52 weeks of rivastigmine treatment.²⁵ A study of memantine use showed a statistically significant improvement in 8 of 16 ADL measures after 12 weeks of treatment.⁴

LTC setting studies provide evidence that CI agents and memantine are associated with decreased behavioral disturbances. A double-blind, parallel-group, placebo-controlled study showed positive trends as measured by the Neuropsychiatric Inventory (NPI) after 6 months of donepezil use.²² In a study by Tariot and colleagues,¹ however, the use of donepezil revealed no significant differences in behavioral problems compared with placebo in patients with high concomitant medication usage. In an open-label study, patients taking rivastigmine showed significant improvement at 26 weeks in neuropsychiatric and behavioral disturbances, such as delusions, hallucinations, agitation, apathy/indifference, irritability/lability, aberrant motor behavior, night-time disturbances, and appetite/eating changes.²⁶ Rivastigmine also improved 10 of 12 individual NPI-Nursing Home domains at 1-year follow-up.²⁵

Because of the risks and side effects in nursing home residents, the use of antipsychotics should be avoided.²⁷ In one study, 40% of patients taking rivastigmine were able to discontinue previous psychotropic medications or reduce the dosage of these medications.¹² In patients with moderate to severe dementia, 12 weeks of memantine treatment was associated with a positive response in the Clinical Global Impression of Change examination, and the Behavioral Rating Scale for Geriatric Patients subscore of care dependence showed an improvement of 3.1 points, whereas the placebo group had an improvement of 1.1 points.⁴ A 3-month open-label pilot study of memantine in LTC facilities showed significant decrease in agitation/aggression, nursing burden, caregiver distress, and the use of psychotropics.²⁸

Pilot Study

The purpose of our study was to assess residents’ conditions and the outcomes of CI and memantine treatment, either alone or in combination, in a Finnish nursing home environment using information collected with the RAI. The RAI was designed to assess and enhance quality of care, estimate the need for resources, and develop payment systems in nursing home settings. It was introduced in Finland in 2000 and was gradually implemented by the Koukkuniemi Home for the Elderly in 2001.²⁹ The RAI has been tested internationally for validity and reliability,^30-32 and it has been found to be useful for research purposes in nursing home settings.^33,34   

Methods

Our pilot study was conducted in the Koukkuniemi Home for the Elderly in Tampere, Finland. We followed 881 nursing home residents living in Koukkuniemi between the years 2001 and 2009. During the study period, CI and memantine were used for patients with Alzheimer’s disease, mixed dementia, Lewy body dementia, and Parkinson’s disease.

Ethical approval for the study was granted by the nursing home institution and by the city of Tampere. Patients were randomly assigned to one of the following four groups: NO, no memantine or cholinesterase inhibitors; M, memantine only; CI, cholinesterase inhibitor only; and C, combination therapy with memantine and a CI. During the course of the study, a patient could remain in only one group. In the M, CI, and C groups, the results of the RAI assessment conducted before starting the agents, or of the resident’s first RAI assessment if he or she had already been taking the medications, were compared with the results of the previous RAI assessment, whether taken before stopping the medication or at the end of the study follow-up if the medication was still being used. In the NO group, this change was calculated over a comparable follow-up time period. For parametric variables, the chi-square and Fisher exact tests were used whenever possible. To assess statistical differences for nonparametric variables, the Kruskal-Wallis and Mann-Whitney U tests were performed. The first was used to assess overall statistical difference between the groups, and the latter was used to compare results between two groups. Statistical significance was defined at the level of P≤.05.

At the Koukkuniemi Home for the Elderly, the RAI assessment is performed by nursing staff every 6 months after a person becomes a nursing home resident or whenever a marked change in health status occurs. As an assessment summary, the instrument provides various scale reports that combine the results of several Minimum Data Set (MDS) questions. For example, the Cognitive Performance Scale (CPS) consists of five different questions that assess short-term memory, ability to be understood, capacity to make decisions, consciousness, and the ability to eat. Reports include the CPS score, the Activities of Daily Living Hierarchy (ADLH), the Depression Rating Scale (DRS), the Social Engagement Scale (SES), the NREHAB scale (measures the rehabilitation provided by nursing staff), pain level, and body mass index (BMI).

In addition, we studied some specific MDS questionnaire items, including the frequency of wandering, negativity toward care, verbal aggression, physical aggression, and inappropriate behavior, all of which are coded in the MDS from 0 to 3 (0=symptom not occurring, 1= occurring 1-3 days a week, 2=occurring 4-6 days a week, and 3=daily symptom). We also examined the frequency of movement restriction in a chair or with bed rails, which is coded using a scale from 0 to 2 (0=not in use, 1=less than daily, and 2=daily use), and assessed residents’ ability to be understood and of understanding, which is coded using a scale from 0 to 3 (0=always, 1=usually, 2=occasionally, and 3=seldom or never). The use of antipsychotics was studied as well from both medical records and from the MDS, with a score of 0 indicating no use and 1 indicating ongoing use.

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Results

Medical records and data from the RAI database of 881 residents living in the Koukkuniemi nursing home were studied. Residents’ mean age was 83.4 years (range, 48.8-105.7 years; Table 1). Mortality was equal in all groups; during the 2 years of follow-up, 24% (n=209) of the residents died. In the first assessment report, the median CPS score was 3, signifying moderate dementia. Only 128 (15%) of the 881 residents were taking specific medication for dementia before moving into the Koukkuniemi nursing home. During the study, about one-half used a CI (18%), memantine (17%), or both (12%). They used these drugs for a mean of 1.6 years (standard deviation, 1.2 years). The CPS scores were lower in the NO group compared with the other groups. The ADLH scores were lower in groups M and C. Pain intensity and severity were rated lower in group C compared with group NO. There were no other statistically significant differences in the first assessment scale reports.

Changes in scale reports. Changes in the scale reports are presented in Table 2. Cognition deteriorated less and the range of changes was smaller in group C. Cognition declined significantly in group CI (P=.001) and in group NO (P=.022) compared with group C and in group CI (P=.03) compared with group M. ADLH points increased the most in group CI compared with all the other groups (NO, P=.003; M, P=.05; C, P=.005). Changes in DRS, SES, NREHAB, BMI, and pain scores showed no significant differences.

Changes in antipsychotic use. Before the first assessment, 47 (5.3%) patients used antipsychotics, namely risperidone and quetiapine. During the follow-up period, antipsychotics were started in 176 (20%) patients and stopped in 138 (15.7%). Before the initiation of CI or memantine, antipsychotics were used more often (P<.001) in group C (21.5%) versus groups NO (0.7%), M (4.5%), and CI (8.7%). On the other hand, during the period a specific dementia medication was used, antipsychotics were started less often (P=.066) in group C (12.1%) versus groups NO (19.0%), M (24.7%), and CI (21.7%). Antipsychotics were stopped more often in group M (P<.001) and in group CI (P<.001) and less often in group NO (7.8%), compared with groups M (28.6%), CI (26.1%), and C (15.0%).

Changes in behavior. In the first assessment, the group differed significantly (P<.05) regarding the presence of wandering, negativity towards care, verbal aggression, physical aggression, and inappropriate behavior, with a lower rate of occurrence in all these measures in group NO. The need for restricting movement to ensure safety while the patient was in a chair was less frequent in group C (P<.05) compared with groups NO and M. During the follow-up, group C had an increase in the rate of wandering and this change differed significantly between groups (NO, P=.000; M, P=.021; CI, P=.003). No significant change was found when studying negativity towards care, verbal aggression, physical aggression, and inappropriate behavior. The need to restrict patient movement for safety by keeping all bed rails up became more common in all groups, with the most pronounced change in group CI (P<.05) compared with groups NO and C. Less need for restricting movement while in a chair was seen in group C compared with group NO (P=.035; Table 3).

During the follow-up, problems in being understood increased 19.2% in group CI, 17.8% in group NO, 17.5% in group M, and 13.0% in group C. Problems in understanding also increased among every group but occurred least often in group C (13.1%) versus groups NO (20.1%), M (23.3%), and CI (24.2%).

Discussion

Our data from the RAI are comprehensive, covering many essential questions concerning the levels of health and function in our residents. RAI benchmarking indicates that the Koukkuniemi nursing home is representative of nursing homes in Finland. Although the data from our study were collected only from one nursing home, the use of a MDS allows generalization of the results to similar facilities. To our knowledge, no other observational study has used RAI data in assessing treatment with CIs plus memantine in an LTC setting.

Regardless of the study group, almost all of the patients in our study had a dementia diagnosis. Relatively few had specific diagnoses or were being treated with any agents for Alzheimer’s disease, mixed dementia, Lewy body dementia, or Parkinson’s disease before moving into the nursing home. Because the mean age of the residents was very high, the symptoms and findings of both Alzheimer’s disease and vascular diseases were common.³⁵ In this population, the prevalence of Alzheimer’s disease and mixed dementia could be estimated to be much higher than 15%, which was the percentage of those who were being treated with a specific medication for dementia before moving into the nursing home.

Memantine or CI agents were started in numerous patients and were in use in almost half of the residents. In a nursing home setting, these medications are usually initiated because of a symptom, such as wandering, negativity towards care, aggression, or inappropriate behavior. These symptoms were more common among the residents whose medication was initiated in the nursing home. The time delay for memantine and CI treatment initiation was equal, but starting combination therapy took longer. In group C, there was significantly more ongoing antipsychotic therapy before the initiation of combination therapy. Patients with the most frequent and severe symptoms became selected for a dementia-specific medication. Differences in the use of antipsychotic therapy, in time delay, and in symptoms may vary the results. This must be considered when interpreting the results of this study.

During the follow-up examination, the time-scale reports showed mainly minor changes. The sensitivity of the RAI in measuring changes may be limited, especially in some areas of the specific scales that are used. For example, studies assessing the correlation between MMSE and CPS scores show that, with a change from a CPS score of 2 to a CPS score of 3, the mean value of the MMSE changes 4 points; but the change from a CPS score of 3 to a CPS score of 4 results in a mean value change of at least 7 points.^36-38 In our study, the median CPS score was 3. Minor deteriorations in cognition may have been missed; however, any change in CPS is clinically relevant. As seen in other studies, although residents’ state of health deteriorated over time, many retained or had improved assessments over a long period.^29,39 In the study by Carpenter and colleagues,³⁹ one-quarter showed an improvement at 6-month follow-up.

The importance of a safe environment and rehabilitative nursing for patients with dementia cannot be underestimated. Significant differences between groups were detected in cognition and in need of assistance in ADL. Cognition deteriorated less in group C compared with groups CI and NO. This finding is in accordance with previous studies.^5-7 Delay for the initiation of specific therapy was the longest in group C, and it could be assumed that the CPS score would deteriorate most in this group, but we found the opposite result. When we compared changes in CPS scores between groups, the C and M groups showed the superiority of memantine. A decline in ADLs was greatest in group CI, but a similar difference was not found in NREHAB scores. The frequency of depressive symptoms as measure by the DRS and in social engagement as measured by SES scores stayed similar in all groups. The psychometric properties of the RAI are still controversial, mainly because the instrument has failed to identify depression in older nursing home residents.⁴⁰

Wandering was more frequent among patients in whom a CI or memantine had been initiated. Its frequency increased significantly in group C compared with other groups. Although residents’ physical activity increased, there was less need for restriction in group C. In accordance with previous findings by Emre and colleagues,⁴¹ problems in communication increased less in group C. Verbal aggression became more frequent in group C, perhaps reflecting an improvement in communication. In a study by Alanen and colleagues,⁴² socially inappropriate or disruptive behavioral symptoms were associated with antipsychotic use, whereas residents with a good sense of initiative or involvement were less likely to be taking such agents. In our study, wandering and verbal aggression were more frequent among residents in group C, and antipsychotics were initiated less often in this group. This finding may be related to the fact that group C exhibited better functional consistency, but it might also be related to the greater use of antipsychotics before initiating combination therapy.

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Conclusion

Several types of scale reports, such as those included in our study, show that many residents with dementia can remain stable for long periods of time after moving to a nursing home. Those treated with combination therapy showed less deterioration in cognition and in communication skills, less increase in the need for restrictions, and less need for new antipsychotics. Patients undergoing therapy with a CI or memantine enabled antipsychotics to be discontinued more often. The results of our study support previous findings that active treatment with a dementia-specific medication seems to be favorable for many patients. CI plus memantine treatment, in the context of patient-specific assessment and follow-up, is recommended for patients with Alzheimer’s disease who are also residing in LTC settings.

Acknowledgement

The authors would like to thank Heini Huhtala, MSc, for helping in the statistical analyses of this report.

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Disclosures:

Dr. Seinelä reports that he has received speaker hononaria from Pfizer, Novartis, Janssen, and Lundbeck, and has been a consultant for Lundbeck. The other authors report no relevant financial relationships.

Address correspondence to:

Lauri K. Seinelä, MD, PhD

Kaakontie 8

33800 Tampere, Finland

lauri.seinela@uta.fi