Clinical Question:
As a Physician Assistant in the Geriatrics Clinic, you frequently encounter patients with dementia, especially Alzheimer’s disease, the most common form. The standard practice in your office is to prescribe Donepezil for patients with mild dementia. However, during Grand Rounds, you heard about the potential benefits of a different class of drug, Memantine. This prompts you to investigate whether the combination of Donepezil and Memantine offers greater benefits for Alzheimer’s patients compared to monotherapy. You conduct a research project to determine if the clinical outcomes are significant enough to apply in practice.
Search Question: Clearly state the question (including outcomes or criteria to be tracked)
In patients with Alzheimer’s disease, does the combination of Donepezil and Memantine, compared to Donepezil monotherapy result in improved clinical outcomes, such as enhanced cognitive and functional abilities and/or slower disease progression?
PICO Question:
Identify the PICO elements – this should be a revision of whichever PICO you have already begun in a previous week.
P | I | C | O |
Alzheimer’s disease | Donepezil and Memantine combination therapy | Monotherapy | Cognitive decline |
Dementia | Donepezil combination therapy | Donepezil monotherapy | Disease progression |
Donepezil dual therapy | Single-agent Donepezil | Clinical outcomes | |
Cholinesterase inhibitor combination | Life Expectancy |
Search Strategy:
Outline the terms used, databases or other tools used, how many articles returned, and how you selected the final articles to base your CAT on. This will likewise be a revision and refinement of what you have already done.
Pubmed
“Memantine” AND “Donepezil” AND “Combination therapy” AND “Monotherapy” AND “Alzheimer’s disease” – 23 results
- (Published in the last 10 years) – 17 Results
Nature
“Donepezil” AND “Memantine” AND “Combination therapy” AND “Alzheimer’s disease” – 28 results
ScienceDirect
“Combination therapy” AND “Cholinesterase inhibitor” AND “Memantine” AND “Alzheimer’s disease”– 344 results
- (Published in the last 10 years) -233 Results
Google Scholar
“Alzheimer’s disease” AND “Donepezil” AND “Memantine” AND “Combination therapy” – 2,860 Results
- (Published in the last 10 years) and (Review Articles) – 815 Results
I aimed to select articles with higher levels of evidence, such as systematic reviews, meta-analyses, or randomized controlled trials (RCTs). If those were unavailable, I prioritized cohort studies next. I ensured that the articles I chose were up-to-date, no older than 10 years. My preference was for studies conducted in the United States. For studies utilizing international data, I restricted my selection to meta-analyses or systematic reviews. I conducted searches across four databases: PubMed, Nature, ScienceDirect, and Google Scholar.
After extensive research, I chose three articles from PubMed—two systematic reviews and meta-analyses, and one pooled analysis of randomized controlled trial data. Additionally, I selected two other systematic review and meta-analysis, one from ScienceDirect and another from Google Scholar. Lastly, a causal inference study using real-world data from one of the largest high-quality medical databases published in Nature Portfolio. All studies selected, except for the systematic reviews and meta-analyses, were published in the United States; however, each review included American studies. All the studies selected for this CAT have been published over the last 10 years.
Articles Chosen (6) for Inclusion (please copy and paste the abstract with link):
Please pay attention to whether the articles address your question and whether they are the highest level of evidence available. If you cannot find high quality articles, be prepared to explain the extensiveness of your search and why there aren’t any better sources available.
1. Guo, J., Wang, Z., Liu, R., Huang, Y., Zhang, N., & Zhang, R. (2020). Memantine, Donepezil, or Combination Therapy-What is the best therapy for Alzheimer’s Disease? A Network Meta-Analysis. Brain and behavior, 10(11), e01831. https://doi.org/10.1002/brb3.1831
Abstract:
Introduction: Alzheimer’s disease (AD) is a degenerative brain disease that progresses over time, heavily burdening patients, families, and aging societies worldwide. Memantine and donepezil are frequently used in its treatment, both as monotherapy and in combination. This multiple treatment comparison meta-analysis assessed the efficacy of these regimens and placebo in the management of AD.
Methods: We searched PubMed, Embase, the Cochrane Library, and Wanfang Med Online and China National Knowledge Infrastructure for English and Chinese publications from the first records to 17 April 2020. Two investigators scanned articles for placebo-controlled trials of memantine and donepezil alone and in combination. We extracted data on the following outcomes: cognition, global assessment, daily activities, neuropsychiatric symptoms, adverse events, and the acceptability and cost of these treatment regimens.
Results: Of 936 records screened, we included 54 trials in this analysis. The combination therapy was more effective in improving cognition (mean difference (MD)-5.01, 95% credible interval (95% Crl) -10.73 to 0.86 in the Alzheimer’s Disease Assessment Scale-Cognitive Subscale; MD 9.61, 95% Crl 2.29 to 16.97 in the Severe Impairment Battery), global assessment (MD -2.88, 95% Crl -6.04 to 0.40), daily activities (MD 13.06, 95% Crl -34.04 to 58.92), and neuropsychiatric symptoms (MD -6.84, 95% Crl -10.62 to -2.82) compared with placebo. Memantine was more acceptable than placebo (MD 0.93, 95% Crl 0.69 to 1.22).
Conclusions: Memantine plus donepezil showed superior outcomes for cognition, global assessment, daily activities, and neuropsychiatric symptoms, but lower acceptability than monotherapy and placebo. Combination therapy may be more cost-effective, because memantine slows the progression of AD.
Keywords: Acceptability of healthcare; Activities of daily living; Alzheimer disease; Cognitive function; Cost effectiveness; Disease progress.
2. Atri, A., Molinuevo, J.L., Lemming, O. et al. Memantine in patients with Alzheimer’s disease receiving donepezil: new analyses of efficacy and safety for combination therapy. Alz Res Therapy 5, 6 (2013). https://doi.org/10.1186/alzrt160
Abstract:
Introduction: Memantine and cholinesterase inhibitors potentially offer additional benefits in Alzheimer’s disease (AD) when used together. This study assessed the efficacy and safety of combination treatment with memantine added to stable donepezil in patients with moderate to severe AD, and in a subset with moderate AD.
Methods: Post hoc meta-analyses of data combined from two 24-week, randomised, double-blind, placebo-controlled trials of memantine 20 mg/day versus placebo, added to a stable cholinesterase inhibitor, were conducted. Data were included for all patients receiving donepezil 10 mg/day with Mini-Mental State Examination (MMSE) scores < 20 (n = 510). Efficacy was assessed using measures of cognition, function, and global status. Furthermore, marked clinical worsening, defined as concurrent deterioration from baseline in the three main efficacy domains, and safety, measured by treatment-emergent adverse events, were assessed. Analyses were performed for patients with moderate to severe AD (MMSE 5-19; MOD-SEV subgroup), and also for patients with moderate AD (MMSE 10-19; MOD subgroup; n = 367).
Results: At week 24, in the MOD-SEV subgroup, patients receiving memantine added to donepezil significantly outperformed those receiving placebo added to donepezil in measures of cognition (P < 0.0001), function (P = 0.02), and global status (P = 0.010), with standardised mean differences (SMDs) of 0.36, 0.21, and 0.23, respectively (all last observation carried forward). Similarly, in the MOD subgroup, significant benefits were observed for cognition (P = 0.008), function (P = 0.04) and global status (P = 0.008), with SMDs of 0.28, 0.21, and 0.28, respectively. Significantly fewer patients receiving memantine added to donepezil showed marked clinical worsening than those receiving placebo added to donepezil, in both subgroups (MOD-SEV: 8.7% versus 20.4%, P = 0.0002; MOD: 5.9% versus 15.0%, P = 0.006). The incidence of adverse events was similar between treatment groups.
Conclusions: These results support and extend previous evidence that combination treatment with memantine added to stable donepezil in patients with moderate AD, and in those with moderate to severe AD, is associated with significant benefits in reducing 24-week decline in cognition, function and global status. Combination treatment produces substantially reduced rates of marked clinical worsening, has good safety and tolerability, and generates effect sizes that are both statistically significant and clinically meaningful.
3. Chen, R., Chan, P. T., Chu, H., Lin, Y. C., Chang, P. C., Chen, C. Y., & Chou, K. R. (2017). Treatment effects between monotherapy of donepezil versus combination with memantine for Alzheimer disease: A meta-analysis. PloS one, 12(8), e0183586. https://doi.org/10.1371/journal.pone.0183586
Abstract:
Background: This is the first meta-analysis to compare the treatment effects and safety of administering donepezil alone versus a combination of memantine and donepezil to treat patients with moderate to severe Alzheimer Disease, particularly regarding cognitive functions, behavioral and psychological symptoms in dementia (BPSD), and global functions.
Methods: PubMed, Medline, Embase, PsycINFO, and Cochrane databases were used to search for English and non-English articles for inclusion in the meta-analysis to evaluate the effect size and incidence of adverse drug reactions of different treatments.
Results: Compared with patients who received donepezil alone, those who received donepezil in combination with memantine exhibited limited improvements in cognitive functions (g = 0.378, p < .001), BPSD (g = -0.878, p < .001) and global functions (g = -0.585, p = .004). Gradual titration of memantine plus a fixed dose and gradual titration of donepezil as well as a fixed dose and gradual titration of memantine resulted in limited improvements in cognitive functions(g = 0.371, p = .005), BPSD(g = -0.913, p = .001), and global functions(g = -0.371, p = .001).
Conclusion: Both in the 24th week and at the final evaluation point, the combination of donepezil and memantine led to greater improvement in cognitive functions, BPSD, and global functions than did donepezil alone in patients with moderate to severe Alzheimer Disease.
4. Serge Gauthier, José L. Molinuevo. Benefits of combined cholinesterase inhibitor and memantine treatment in moderate–severe Alzheimer’s disease, Alzheimer’s & Dementia, Volume 9, Issue 3, 2013, Pages 326-331, ISSN 1552-5260, https://doi.org/10.1016/j.jalz.2011.11.005 (https://www.sciencedirect.com/science/article/pii/S1552526011030457)
Abstract:
Background: Clinical studies and post hoc analyses have investigated the use of combination therapy for the treatment of Alzheimer’s disease (AD). We review the evidence for the short- and long-term efficacy of combination therapy in AD.
Methods: The review is based on a search of the PubMed database to identify relevant articles concerning combination treatment with memantine and cholinesterase inhibitors (ChEIs).
Results: In patients with moderate-to-severe AD, combination treatment with the N-methyl-d-aspartate receptor antagonist memantine and the ChEI donepezil has produced significant benefits in cognition, function, behavior, global outcome, and care dependency, compared with donepezil treatment alone. Data from long-term observational studies support these findings. Compared with ChEI monotherapy, combination treatment slowed cognitive and functional decline (a 4-year sustained effect that appeared to increase over time) and reduced the risk of nursing home admission. Preclinically, the combination of N-methyl-d-aspartate receptor modulation and acetylcholinesterase inhibition has been shown to act synergistically, which may explain the observed clinical effects of combination treatment.
Conclusion: Treatment with memantine/ChEI combination therapy in moderate-to-severe AD produces consistent benefits that appear to increase over time, and that are beyond those of ChEI treatment alone.
5. Atri, A., Hendrix, S. B., Pejović, V., Hofbauer, R. K., Edwards, J., Molinuevo, J. L., & Graham, S. M. (2015). Cumulative, additive benefits of memantine-donepezil combination over component monotherapies in moderate to severe Alzheimer’s dementia: a pooled area under the curve analysis. Alzheimer’s research & therapy, 7(1), 28. https://doi.org/10.1186/s13195-015-0109-2
Abstract:
Introduction: Treatment in moderate or severe Alzheimer’s disease (AD) often involves adding memantine to a cholinesterase-inhibitor (ChEI: donepezil, galantamine, rivastigmine). Evidence from six-month randomized trials and long-term observational studies supports superiority of memantine-ChEI combination to ChEI monotherapy. We utilized area-under-the-curve (AUC) analysis to assess six-month cumulative treatment efficacy of memantine-donepezil combination versus component monotherapies on individual clinical domains and on a composite index.
Methods: Data were pooled from 1,408 individuals with moderate to severe AD from four six-month randomized trials of memantine monotherapy (n = 570) or add-on therapy (donepezil-only subset: n = 847). AUC changes from baseline on measures of cognition (SIB), function (ADCS-ADL19), behavior (NPI), global status (CIBIC-Plus), and a composite index (4D-CI: equally weighted composite of four domain measures) were calculated using the trapezoidal rule and evaluated via analysis of covariance (ANCOVA) (2-sided-α = 0.05). AUC results were contrasted with visit-by-visit changes from baseline (“snapshot analysis”), performed using a mixed-effects model with repeated measures (MMRM).
Results: Over the entire six-month period, placebo-only treatment was associated with significant cumulative worsening on all outcomes. Memantine-donepezil combination showed significantly greater AUC improvements (point x week) on the SIB, NPI, and CIBIC-Plus than placebo-donepezil (SIB: 68.4 versus 32.0, P = 0.019; NPI: -74.3 versus -28.2, P = 0.003; CIBIC-Plus: -2.5 versus 1.4, P = 0.006) and memantine-only monotherapies (SIB: 68.4 versus 12.0, P <0.001; NPI: -74.3 versus -7.4, P <0.001; CIBIC-Plus: -2.5 versus 2.7, P <0.001), whereas these comparisons were not significant for the ADCS-ADL19 (memantine-donepezil (1.4) versus placebo-donepezil (-0.9), P = 0.407; versus memantine-only (-12.2), P = 0.310). Composite index analysis demonstrated significant cumulative advantages of memantine-donepezil combination (630.0) over placebo-donepezil (344.7, P <0.001) and memantine-only (152.1, P <0.001) treatments. Combining memantine and donepezil had an additive effect. Compared with AUC analysis, baseline-to-endpoint change-score analysis underestimated effects of combination therapy, monotherapies, or both.
Conclusions: This large pooled area-under-the-curve analysis of randomized-trial data in moderate to severe AD provides ecologically valid support that adding memantine to stable donepezil results in overall clinical benefits that are additive compared with individual monotherapies, continue to accumulate through six-month treatment, and are at least 50% greater than those of monotherapies.
6. Yaghmaei, E., Lu, H., Ehwerhemuepha, L. et al. Combined use of Donepezil and Memantine increases the probability of five-year survival of Alzheimer’s disease patients. Commun Med 4, 99 (2024). https://doi-org.york.ezproxy.cuny.edu/10.1038/s43856-024-00527-6
Abstract:
Background: Alzheimer’s disease (AD) is the most common neurodegenerative disease. Studying the effects of drug treatments on multiple health outcomes related to AD could be beneficial in demonstrating which drugs reduce the disease burden and increase survival.
Methods: We conducted a comprehensive causal inference study implementing doubly robust estimators and using one of the largest high-quality medical databases, the Oracle Electronic Health Records (EHR) Real-World Data. Our work was focused on the estimation of the effects of the two common Alzheimer’s disease drugs, Donepezil and Memantine, and their combined use on the five-year survival since initial diagnosis of AD patients. Also, we formally tested for the presence of interaction between these drugs.
Results: Here, we show that the combined use of Donepezil and Memantine significantly elevates the probability of five-year survival. In particular, their combined use increases the probability of five-year survival by 0.050 (0.021, 0.078) (6.4%), 0.049 (0.012, 0.085), (6.3%), 0.065 (0.035, 0.095) (8.3%) compared to no drug treatment, the Memantine monotherapy, and the Donepezil monotherapy respectively. We also identify a significant beneficial additive drug-drug interaction effect between Donepezil and Memantine of 0.064 (0.030, 0.098).
Conclusions: Based on our findings, adopting combined treatment of Memantine and Donepezil could extend the lives of approximately 303,000 people with AD living in the USA to be beyond five-years from diagnosis. If these patients instead have no drug treatment, Memantine monotherapy or Donepezil monotherapy they would be expected to die within five years.
Summary of Evidence:
Conclusion(s):
– Briefly summarize the conclusions of each article, then provide an overarching conclusion.
Author (Date) | Level of Evidence | Sample/Setting (# of subjects/ studies, cohort definition etc.) | Outcome(s) studied | Key Findings | Limitations and Bias |
Guo, J., Wang, Z., Liu, R., Huang, Y., Zhang, N., & Zhang, R. (2020) | Systematic Review and Meta-analysis | – Databases searched, PubMed, Embase, the Cochrane Library, Wanfang Med Online, China National Knowledge Infrastructure – 936 records screened -54 trials included in the analysis -Investigated memantine, donepezil, and their combination | – Cognition, Evaluated using the Alzheimer’s Disease Assessment Scale-cognition subscale and the Severe Impairment Battery. – Global Assessment, measured by changes in the Clinical Global Impression -Daily Activities, Assessed through the Alzheimer’s Disease Cooperative Study-Activities of Daily Living and Activities of Daily Living (ADL) scales. – Neuro-psychiatric Symptoms, Examined using the Neuro-psychiatric Inventory. -Acceptability, Determined by the rate of treatment discontinuation due to factors such as dissatisfaction with treatment, deterioration of the patient’s condition, or adverse events. – Costs, direct costs (related to treatment and caregiving) and indirect costs (such as lost productivity). | – Combination therapy of donepezil and memantine was most effective in improving cognition, global assessment, daily activities, and neuropsychiatric symptoms in Alzheimer’s disease patients. – Memantine combined with donepezil showed efficacy in both mild and severe dementia. -The combination therapy outperformed placebo on the Clinical Global Impression (CGI) scale. -In daily living activities, memantine plus donepezil was most effective. -Memantine plus donepezil was superior improving neuropsychiatric symptoms. | – The quality of some included trials was not high, potentially affecting the meta-analysis results. – The study only searched published trials, excluding databases like the Cochrane Central Register of Controlled Trials, leading to potential publication bias and overestimation of outcomes. |
Atri, A., Molinuevo, J.L., Lemming, O. et al. (2013) | Meta-analysis | – Two 24-week, randomized, double-blind, placebo-controlled trials of memantine 20 mg/day versus placebo, added to a stable cholinesterase inhibitor, were conducted. – Data were included for all patients receiving donepezil 10 mg/day with Mini-Mental State Examination (MMSE) scores < 20 (n = 510). – Total of 510 patients receiving donepezil 10 mg/day with Mini-Mental State Examination (MMSE) scores < 20. Patients 50 years or older with probable AD, stable cholinesterase inhibitor ttreatment for at least 6 months. | – Efficacy was assessed using measures of cognition, function, and global status. – Marked clinical worsening, defined as concurrent deterioration from baseline in the three main efficacy domains, and safety, measured by treatment-emergent adverse events, were assessed. | – In the moderate to severe Alzheimer’s disease subgroup, patients receiving memantine added to donepezil showed significant improvements in cognition (P < 0.0001), function (P = 0.02), and global status (P = 0.010) compared to those receiving placebo added to donepezil. -In the moderate Alzheimer’s disease subgroup, significant benefits were observed for cognition (P = 0.008), function (P = 0.04), and global status (P = 0.008) with memantine added to donepezil. – Fewer patients on memantine added to donepezil experienced marked clinical worsening. | – The use of the Mini-Mental State Examination (MMSE) as a proxy for disease stage focuses solely on cognition, which is only one domain of Alzheimer’s disease symptoms and is measured in a limited way. -Measuring “marked clinical worsening” may not capture significant decline in all patients -The 24-week duration of the trials is shorter than the typical duration of treatment in real-world clinical practice and may not fully capture the long-term risk-benefit balance of combination therapy. |
Chen, R., Chan, P. T., Chu, H., Lin, Y. C., Chang, P. C., Chen, C. Y., & Chou, K. R. (2017) | Meta-Analysis | – PubMed, Medline, Embase, PsycINFO, and Cochrane databases were used to search for English and non-English articles for inclusion in the meta-analysis to evaluate the effect size and incidence of adverse drug reactions of different treatments. -2,374 articles initially identified and 11 studies included in the meta-analysis. | – Treatment effects on cognitive functions and behavioral and psychological symptoms of dementia at the final evaluation point. – Comparison of donepezil alone versus combination treatment with memantine and donepezil after 24 weeks. – Evaluation of treatment effects based on memantine dosing (gradual titration vs. fixed dose) on cognitive functions, behavioral and psychological symptoms of dementia and global functions. | – Patients receiving donepezil plus memantine significant improvements in cognitive functions (effect size g = 0.378, p < .001). – Combination treatment resulted in significant reductions in behavioral and psychological symptoms of dementia (effect size g = -0.878, p < .001). – The combination therapy also led to moderate improvements in global functions (effect size g = -0.585, p = .004). | -Heterogeneity across studies, and the sample size varied among the investigated studies. – The conclusions were still limited because of the small sample size. |
Serge Gauthier, José L. Molinuevo. (2013) | Systematic Review | – PubMed was utilized to identify relevant articles and with original information on treatment effects of combination therapy for Alzheimer’s Disease. – A specific clinical study mentioned involved 404 patients with moderate-to-severe Alzheimer’s Disease. – Participants had a Mini-Mental State Examination (MMSE) score between 5 and 14. | – Evaluated the efficacy, safety, and tolerability of combination treatment with memantine and cholinesterase inhibitors. – Measured cognition, function, behavior, global outcome, and the level of care dependency. | – In patients with moderate-to-severe Alzheimer’s disease, combination treatment with memantine (an N-methyl-d-aspartate receptor antagonist) and donepezil (a cholinesterase inhibitor) resulted in significant improvements in cognition, function, behavior, and global outcome care dependency – Long-term observational studies corroborate the benefits of combination treatment over donepezil monotherapy. -The combination treatment was found to slow cognitive and functional decline compared to cholinesterase inhibitor monotherapy. | – The majority of data are derived from only two prospective clinical studies. -Observational data are also limited by being nonrandomized and uncontrolled, although they do reflect the effects of AD treatment in a naturalistic setting over an extended period. |
Atri, A., Hendrix, S. B., Pejović, V., Hofbauer, R. K., Edwards, J., Molinuevo, J. L., & Graham, S. M. (2015). | Pooled analysis of random-ized controlled trial data | – Data pooled from 1,408 individuals with moderate to severe Alzheimer’s disease. – Participants had a combined protocol-specified Mini Mental State Exam (MMSE) score ranging from 3 to 14. – Treatment groups included placebo, memantine, no cholinesterase inhibitors, stable donepezil therapy, stable doses of any cholinesterase inhibitors. | – Included measures of cognition, function, behavior, and global clinical status. | – The memantine-donepezil combination demonstrated significantly greater area under the curve (AUC) improvements in all measurements when compared to placebo-donepezil, and memantine- only treatment. – The combination therapy of memantine and donepezil had an additive effect on improving outcomes. | – The pooled trials had a treatment duration of only six months, which is shorter than the typical treatment periods in clinical practice. This limitation highlights the need for long-term studies. – Long-term studies are essential for guiding therapeutic discovery efforts and improving treatment strategies. |
Yaghmaei, E., Lu, H., Ehwerhemuepha, L. et al. (2024) | Inference study using real-world data from one of the largest high-quality medical databases | – Oracle Electronic Health Records (EHR) Real-World Data, a large, high-quality medical database with over 100 million patients and 1.5 billion encounters. – Cohort of 17,855 patients with at least five years of follow-up. Removed 4,338 (24.3%) patients who switched treatments during the study period. Final cohort size: 12,744 patients. | – Five-year survival since the initial diagnosis of Alzheimer’s disease. – Calculated unadjusted mortality rates per treatment group per 1000 patient-years. – Focused on Donepezil, Memantine, and their combined use, with a control group receiving no drug treatment. | – The combined use of Donepezil and Memantine significantly elevates the probability of five-year survival for Alzheimer’s disease patients, over no drug treatment, memantine monotherapy, donepezil monotherapy. | – The study didn’t take into account potential confounding factors, as the study relied on electronic health records without including lifestyle factors, genetic data, or environmental exposures that could influence treatment and survival. – Exclusion of 24.3% of the original sample due to treatment switching, highlighting a need for analyses involving time-varying treatments. |
Guo, J., Wang, Z., Liu, R., Huang, Y., Zhang, N., & Zhang, R. (2020): This meta-analysis, included 54 studies across Asia, North America, and Europe, found that the combination of donepezil and memantine is more effective than donepezil monotherapy in improving clinical outcomes for Alzheimer’s disease patients, particularly those with moderate to severe AD. The combination therapy significantly improved cognition, global assessments, activities of daily living, and neuropsychiatric symptoms. While it demonstrated slightly higher acceptability than donepezil alone, the overall efficacy across multiple domains suggests it offers substantial benefits. Additionally, although donepezil was less well-tolerated, the combination therapy was still a viable option for patients, especially considering its potential to slow disease progression.
Overarching conclusion: The combination of donepezil and memantine results in improved outcomes compared to donepezil monotherapy for patients with Alzheimer’s disease. The combination therapy is superior in enhancing cognition, global function, daily activities, and neuropsychiatric symptoms, making it a preferred treatment option for those with moderate to severe AD.
Atri, A., Molinuevo, J.L., Lemming, O. et al. (2013): This study shows the benefits of adding memantine to stable donepezil therapy for patients with moderate to severe Alzheimer’s disease. Analyzing data from 510 patients across randomized controlled trials, the findings revealed clinically meaningful effect sizes in various efficacy domains, including cognition, function, and global status, favoring combination therapy over donepezil monotherapy. Findings support the notion that the combination treatment contributes to a slower decline in cognitive and functional abilities. The results have practical relevance of using memantine in conjunction with donepezil to potentially allow individuals to maintain independence longer.
Overarching conclusion: The addition memantine to donepezil therapy not only enhances cognitive and functional abilities but also helps to prevent significant clinical decline, making it a recommended treatment approach over donepezil monotherapy in this patient population.
Chen, R., Chan, P. T., Chu, H., Lin, Y. C., Chang, P. C., Chen, C. Y., & Chou, K. R. (2017): This study found that the combination of memantine and donepezil in patients with moderate to severe Alzheimer’s disease resulted in greater improvements in cognitive functions, behavioral and psychological symptoms of dementia, and global functions compared to donepezil monotherapy. Importantly, there was no significant difference in adverse drug reactions between the combination treatment and monotherapy groups, indicating that the combination therapy did not pose additional safety risks.
Overarching conclusion: The combination of memantine and donepezil demonstrates greater clinical efficacy in treating cognitive decline compared to donepezil alone, without increasing the risk of adverse reactions.
Serge Gauthier, José L. Molinuevo. (2013): In patients with moderate-to-severe Alzheimer’s disease, the combination of memantine and donepezil produces significant improvements in cognition, function, behavior, and overall clinical outcomes, compared to donepezil monotherapy. Combination therapy not only slowed cognitive and functional decline over four years but also reduced the risk of nursing home admission. Additionally, it helped maintain independence in daily activities and delayed the emergence of challenging behaviors such as agitation and aggression.
Overarching conclusion: Combination of memantine and donepezil offers consistent advantages in treating moderate-to-severe AD compared to donepezil alone with benefits increasing over time.
Atri, A., Hendrix, S. B., Pejović, V., Hofbauer, R. K., Edwards, J., Molinuevo, J. L., & Graham, S. M. (2015): The pooled area under the curve analysis of over 1,400 patients from four randomized controlled trials in moderate-to-severe Alzheimer’s disease demonstrates that the combination of memantine and donepezil provides multiple benefits over six months, superior to either drug alone. Across cognition, daily functioning, behavior, and global clinical status, the combination therapy consistently outperformed monotherapy with either memantine or donepezil. Analysis showed long-term advantages of combination therapy. Although some differences in cognitive outcomes between donepezil and memantine monotherapy were observed, overall, the combination therapy provided a significant improvement compared to monotherapy and placebo.
Overarching conclusion: Memantine and donepezil leads to superior clinical outcomes compared to monotherapy in patients with AD.
Yaghmaei, E., Lu, H., Ehwerhemuepha, L. et al. (2024): This study used a causal inference to investigate the impact of combining donepezil and memantine on the survival of Alzheimer’s disease patients. The findings demonstrated that the combination therapy significantly increased the probability of five-year survival compared to monotherapies or no treatment. It was estimated that the combination treatment could extend the lives of current AD patients in the U.S. beyond five years, with further potential benefits for future populations. Limitations such as potential confounding factors exist in this study.
Overarching conclusion: The study provides evidence that combination therapy with donepezil and memantine improves survival outcomes in AD patients, suggesting a clinical benefit and advantage over donepezil monotherapy.
Clinical Bottom Line:
Please include an assessment of the following:
– Weight of the evidence – summarize the weaknesses/strengths of the articles and explain how they factored into your clinical bottom line (this may recap what you discussed in the criteria for choosing the articles)
– Magnitude of any effects
– Clinical significance (not just statistical significance)
– Any other considerations important in weighing this evidence to guide practice – If the evidence you retrieved was not enough to conclude an answer to the question, discuss what aspects still need to be explored and what the next studies will have to answer/provide (e.g. larger number, higher level of evidence, answer which sub-group benefits, etc)
Guo, J., Wang, Z., Liu, R., Huang, Y., Zhang, N., & Zhang, R. (2020): Among the six studies, I consider this one the strongest in terms of evidence, as it is a recent meta-analysis that included 54 trials. It showed that combination therapy was more effective in improving cognition (mean difference (MD) −5.01, 95% credible interval (CrI) −10.73 to 0.86 on the Alzheimer’s Disease Assessment Scale-Cognitive Subscale; MD 9.61, 95% CrI 2.29 to 16.97 on the Severe Impairment Battery), global assessment (MD −2.88, 95% CrI −6.04 to 0.40), daily activities (MD 13.06, 95% CrI −34.04 to 58.92), and neuropsychiatric symptoms (MD −6.84, 95% CrI −10.62 to −2.82) compared to monotherapy. These findings demonstrate both statistically and clinically significant improvements in cognition, global function, daily activities, and neuropsychiatric symptoms for combination therapy. In terms of cognitive improvement, combination therapy showed the greatest benefit, with the ADAS-Cog (MD −5.01, 95% CrI −10.73 to 0.86) and SIB (MD 9.61, 95% CrI 2.29 to 16.97) scales outperforming both donepezil and memantine monotherapy. Despite some tolerability issues with donepezil, combination therapy remains a viable option, offering substantial benefits and potentially slowing disease progression. However, there are limitations that may affect the strength of these findings. The quality of some included trials was low, which could influence the results. Additionally, the study only included published trials and did not search databases like the Cochrane Central Register of Controlled Trials, potentially introducing bias and overestimating the benefits of combination therapy.
Chen, R., Chan, P. T., Chu, H., Lin, Y. C., Chang, P. C., Chen, C. Y., & Chou, K. R. (2017): Out of the six studies, I would rate this one as the second strongest in terms of evidence because it is a meta-analysis of 2,374 articles initially identified, 11 studies were included. Patients receiving donepezil combined with memantine showed significant improvements in clinical outcomes, particularly in cognitive functions, behavioral and psychological symptoms of dementia (BPSD), and global functional abilities. For cognitive functions, combination therapy demonstrated superiority (Hedges’ g = 0.378, 95% CI: 0.193–0.562, p < .001, I² = 57.145). Sensitivity analysis confirmed these results, even after excluding a study by Shao, which slightly reduced heterogeneity (Hedges’ g = 0.331, I² = 43.494), suggesting that combination therapy is statistically more effective than monotherapy or placebo in enhancing cognitive outcomes, with no evidence of publication bias (p = .375). For BPSD, combination therapy also showed significant superiority over monotherapy, with a large effect size (Hedges’ g = −0.878, 95% CI: −1.256 to −0.500, p < .001, I² = 82.116). Global functional outcomes were significantly improved with combination therapy compared to monotherapy (Hedges’ g = −0.585, 95% CI: −0.981 to −0.188, p = .004, I² = 87.358). These findings suggest that while combination therapy provides statistically significant improvements in cognitive, behavioral, and functional outcomes compared to monotherapy, the clinical significance should be carefully evaluated due to factors like heterogeneity, which varied across the studies.
Atri, A., Molinuevo, J.L., Lemming, O. et al. (2013): Of all six studies, I would rank this one as the third strongest because it is a meta-analysis that combined data from two 24-week randomized, double-blind, placebo-controlled trials, in which memantine was added to stable cholinesterase inhibitors. Clinical outcomes were assessed across cognitive, functional, and global status domains using validated measures: the Severe Impairment Battery (SIB) and ADAS-Cog for cognition, the AD Cooperative Study-Activities of Daily Living (ADCS-ADL23 and ADCS-ADL19) for function, and the Clinician’s Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) for global status. These tools quantified treatment effects in a subgroup of 510 patients with moderate to severe Alzheimer’s disease (MMSE scores 5–19), with additional analysis for a moderate subgroup (MMSE scores 10–19). In the moderate-to-severe subgroup, patients receiving memantine plus donepezil significantly outperformed those receiving placebo plus donepezil in measures of cognition (P < 0.0001), function (P = 0.02), and global status (P = 0.010), with standardized mean differences (SMDs) of 0.36, 0.21, and 0.23, respectively. Similar results were observed in the moderate group. Fewer patients receiving combination therapy experienced marked clinical worsening compared to those receiving placebo plus donepezil in both subgroups (MOD-SEV: 8.7% versus 20.4%, P = 0.0002; MOD: 5.9% versus 15.0%, P = 0.006). Limitations include the fact that measuring “marked clinical worsening” may not fully capture significant declines in all patients. Additionally, the 24-week duration of the trials is shorter than typical treatment durations in real-world clinical practice, potentially limiting the assessment of the long-term risk-benefit balance of combination therapy. Overall, this study demonstrates the benefits of adding memantine to stable donepezil therapy for patients with moderate to severe Alzheimer’s disease, where combination treatment slows the decline in cognitive and functional abilities, allowing individuals to maintain their independence longer.
Serge Gauthier, José L. Molinuevo. (2013): Of all six studies, I would rank this one as the fourth strongest due to its systematic review design and a sample size of 404 patients with moderate-to-severe Alzheimer’s disease. The combination therapy of donepezil and memantine has demonstrated statistically significant benefits for moderate-to-severe Alzheimer’s disease compared to donepezil monotherapy. For instance, there was a significant difference in improvement in the language, praxis, and memory subscales of the Severe Impairment Battery, with scores showing a mean difference favoring combination therapy (0.9 ± 0.67 vs. -2.5 ± 0.69, p < 0.001). Higher-order cognitive functions, including memory, attention, language, social interaction, and visuospatial ability, also showed significant improvements (P ≤ 0.01). Functional improvements, such as toileting, grooming, and watching television, measured by the Alzheimer’s Disease Cooperative Study-Activities of Daily Living 19-item subscale (ADCS-ADL19), also showed a significant benefit favoring combination therapy (-2.0 ± 0.50 vs. -3.4 ± 0.51, p = 0.03). Behavioral symptoms favored combination therapy as well, with significant reductions in agitation/aggression, irritability/lability, and appetite/eating changes (p < 0.05), showing marked advantages in behavioral domains. However, the study has limitations, as most data are derived from only two prospective clinical studies, which may restrict the generalizability of the findings. Additionally, the observational data are nonrandomized and uncontrolled, potentially introducing bias; nevertheless, they offer valuable insights into Alzheimer’s disease treatment effects in a naturalistic setting over an extended period. Overall, for patients with moderate-to-severe Alzheimer’s disease, the combination of memantine and donepezil significantly enhances cognition, function, behavior, and overall clinical outcomes compared to donepezil monotherapy. This therapy slows cognitive and functional decline over four years, reduces the risk of nursing home admission, maintains independence in daily activities, and delays challenging behaviors such as agitation and aggression.
Atri, A., Hendrix, S. B., Pejović, V., Hofbauer, R. K., Edwards, J., Molinuevo, J. L., & Graham, S. M. (2015): I would rank this study second to last, mainly because it is not a meta-analysis or review, but a pooled analysis of randomized controlled trial data from 1,408 individuals with moderate-to-severe Alzheimer’s disease. Over a six-month period, the memantine-donepezil combination showed significantly greater improvements on the Severe Impairment Battery (SIB), Neuropsychiatric Inventory (NPI), and Clinician’s Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) compared to placebo-donepezil (SIB: 68.4 vs. 32.0, P = 0.019; NPI: −74.3 vs. −28.2, P = 0.003; CIBIC-Plus: −2.5 vs. 1.4, P = 0.006) and memantine-only monotherapy (SIB: 68.4 vs. 12.0, P < 0.001; NPI: −74.3 vs. −7.4, P < 0.001; CIBIC-Plus: −2.5 vs. 2.7, P < 0.001). However, these comparisons were not significant for the ADCS-ADL19 scale (memantine-donepezil: 1.4 vs. placebo-donepezil: −0.9, P = 0.407; vs. memantine-only: −12.2, P = 0.310). The results showed both statistical and clinical significance for combination therapy. Statistically significant improvements (P < 0.05) were observed across primary outcomes, with relative AUC improvements compared to placebo ranging from 104.4% (ADCS-ADL19) to 459.3% (4D-CI). These improvements were clinically meaningful, as combination therapy demonstrated additive effects rather than synergistic ones, with cumulative benefits exceeding those of monotherapy or placebo. The sustained cognitive and functional improvements and slower disease progression of combination therapy prove clinical relevance. A limitation of this study is that the pooled trials had a treatment duration of only six months, which is shorter than typical treatment periods in clinical practice and may not fully capture the long-term efficacy and safety of combination therapy. In conclusion, while some cognitive differences were noted between donepezil and memantine monotherapy, overall, combination therapy offered greater improvements than monotherapy or placebo.
Yaghmaei, E., Lu, H., Ehwerhemuepha, L. et al. (2024): I would rank this study last in terms of strength of evidence because it is not one of the highest-evidence studies, but rather an inference study that used real-world data from one of the largest high-quality medical databases, the Oracle Electronic Health Records, with a final cohort of 12,744 patients. The treatment comparison analysis revealed that combination therapy significantly increased five-year survival rates compared to all other groups. Quantifiable measures, including standardized mean differences, counterfactual probabilities, and risk ratios, support these findings. Compared to no drug use, combination therapy improved survival by 5% (6.4%), with a Bonferroni-adjusted 95% CI [0.021, 0.078]. Relative to memantine monotherapy, the increase was 4.9% (6.3%), 95% CI [0.012, 0.085], and compared to donepezil monotherapy, the increase was 6.5% (8.3%), 95% CI [0.035, 0.095]. These findings were reinforced by statistically significant risk ratios of 1.064 (95% CI [1.026, 1.100]), 1.063 (95% CI [1.016, 1.112]), and 1.085 (95% CI [1.045, 1.126]) for combination therapy versus no drug, memantine alone, and donepezil alone, respectively. Additionally, the drug interaction analysis revealed a significant synergistic effect between donepezil and memantine, with an estimated interaction value of 0.064 (95% CI [0.030, 0.098]). In conclusion, the study provides strong evidence of statistically significant and clinically meaningful improvements in survival with combination therapy, emphasizing its potential to enhance cognitive and functional outcomes in patients with Alzheimer’s disease. However, the study did not account for potential confounding factors that could influence treatment and survival outcomes. Additionally, cognitive improvement and other clinical outcomes were not measured, though survival probability is a measurable clinical outcome to assess treatment effectiveness. Overall, combining donepezil and memantine significantly improved five-year survival rates in Alzheimer’s patients compared to monotherapies or no treatment, with potential benefits for extending life expectancy in current and future U.S. populations.
Based on the conclusions from six studies, the combination of donepezil and memantine demonstrates superior clinical outcomes, offering statistically and clinically significant benefits across cognitive, functional, and behavioral domains compared to donepezil monotherapy in patients with moderate-to-severe Alzheimer’s disease.
Guo et al. (2020) found that combination therapy significantly improves cognition, global function, daily activities, and neuropsychiatric symptoms compared to monotherapy, slowing disease progression as evidenced by improvements on the ADAS-cog (MD 5.01, 95% CrI −0.86 to 10.73) and SIB (MD 9.61, 95% CrI 2.29 to 16.97). Similarly, Atri et al. (2013) showed that patients receiving memantine plus donepezil outperformed those receiving placebo plus donepezil in cognition (P < 0.0001), function (P = 0.02), and global status (P = 0.010), indicating slowed cognitive and functional decline. Chen et al. (2017) further supported these findings, reporting that combination therapy resulted in greater improvements in cognitive outcomes (Hedges’ g = 0.378, 95% CI: 0.193–0.562, p < .001) and behavioral symptoms (Hedges’ g = −0.878, 95% CI: −1.256 to −0.500, p < .001), with no additional safety concerns. Gauthier and Molinuevo (2013) observed consistent advantages of the combination therapy, reporting significant improvements in the language, praxis, and memory subscales of the Severe Impairment Battery (mean difference: 0.9 ± 0.67 vs. −2.5 ± 0.69, p < 0.001). Atri et al. (2015) pointed out both short- and long-term benefits, showing sustained improvements in cognition (SIB: 68.4 vs. 32.0, P = 0.019), neuropsychiatric symptoms (NPI: −74.3 vs. −28.2, P = 0.003), and global impressions (CIBIC-Plus: −2.5 vs. 1.4, P = 0.006), with combination therapy consistently outperforming placebo and donepezil monotherapy. Lastly, Yaghmaei et al. (2024) found that combination therapy displayed a synergistic effect, with a 6.5% increase in five-year survival compared to donepezil monotherapy (95% CI [0.035, 0.095]), suggesting life-extending benefits.
In conclusion, for patients with moderate-to-severe Alzheimer’s disease, the combination of donepezil and memantine consistently demonstrates significant advantages over monotherapy across all studies. It not only enhances cognitive and functional abilities but also offers long-term benefits, including slowing disease progression, maintaining independence, reducing nursing home admissions, and extending survival.
Final-CAT