Studies in dementia treatment thus far have yielded findings that suggest modest benefits using ChEI in combination with memantine in patients with AD based on the effect sizes. The pooled results in this review showed that there was no statistically significant change on the continuous outcome measures of cognition in patients with mild to severe dementia. Study patients had MMSE ranges of 5–14 in Tariot et al. [13
], 5–13 in Howard et al. [21
], and 10–22 in Porsteinsson et al. [20
]; thus, all groups had some overlap in severity of dementia. The 3 trials lacked clear definitions of how mild to moderate disease is discriminated from moderate to severe disease, apart from the MMSE scores. Because of these issues, analyzing all levels of severity was warranted prior to the subgroup analysis. A statistically significant effect size in favor of combination therapy was appreciated in the subgroup analysis when patients with mild to moderate disease were excluded. The study by Tariot et al. [13
], which found statistically significant improvement, measured cognition using the SIB, which is geared towards patients with advanced dementia, avoiding the floor effect [31
] that can occur with the MMSE in similar patients. The floor effect may have attenuated the results of the DOMINO trial, which used the MMSE in its cohort of moderate to severe AD patients. In the DOMINO trial, combination therapy was not significantly better than donepezil alone, and it did not result in an MMSE change as large as when continuing monotherapy with either donepezil or memantine. This latter finding highlights what is already current practice, namely the positive effect of memantine in moderate to severe disease [32
], and also suggests a potential role for the continuation of donepezil monotherapy rather than its discontinuation.
Although the cohort studies in general did not provide detailed information on the severity of AD in their patients, the article by Schneider et al. [27
], which included patients with mild AD, did not show benefit with combination therapy. A similar pattern was appreciated among the open-label trials as well; the study by Riepe et al. [24
] included mild to moderate disease, and although there was an observed benefit, it was most evident at the more severe end of the cognitive spectrum. In the study by Atri et al. [12
], patients on therapy were assessed between 1997 and 2005; this suggests heterogeneity between patients enrolled in the study, as both pharmacological and non-pharmacological conservative interventions for relevant risk factors may have changed over the years.
Meta-analysis of the functional outcome scales from the 3 blinded-RCTs using the standardized mean difference showed a significant effect size in favor of combination therapy when the monotherapy arm of the DOMINO trial was memantine, but not when it was donepezil. This is probably explained by the large weight Tariot et al. [13
] carried in the analysis (~70%) in this comparison, thus requiring a conservative interpretation of the result, whereas the weight was more evenly distributed when the monotherapy arm was donepezil and the result was not significant (fig. ). Tariot et al. [13
] also carried significant weight in the moderate to severe subgroup analyses. The study showed improvement in their patients with moderate to severe dementia as measured with the ADSC-ADL19
, while no improvement was seen in the Porsteinsson et al. [20
] study with patients in the mild to moderate range and measured by the ADCS-ADL23
. Each of these studies used a version of the ADCS-ADL that is the most suited to detect change in their population [33
], as did the DOMINO trial which used the BADL. Additionally, the study by Porsteinsson et al. [20
] used the ADCS-ADL23
as a secondary outcome measure. In the few cohort and open-label studies that found improvement in functional outcomes, patients’ condition varied in severity, but they were mainly in the moderate to severe range; however, no improvement was observed on caregiver assessment of ADL. The CIBIC-Plus results revealed statistically significant improvements in the moderate to severe AD patients from the Tariot et al. [13
] study, where it was a primary outcome measure, and no improvement in the mild to moderate AD patients from the Porsteinsson et al. [20
] study, where it was a secondary outcome measure. In addition to these measurement discrepancies, there has been concern about the reliability of the CIBIC-Plus and its relative insensitivity to detect change [34
Three out of the 4 subgroup analyses assessing the neurobehavioral outcomes with the NPI showed that it was statistically significant in favor of combination therapy (fig. ). Interestingly, the NPI was significant in the more advanced dementia groups from Tariot et al. [13
], and when combination was compared with memantine monotherapy, in Howard et al. [21
]. There is some concern about variability in administration and scoring of the NPI [37
]. The NPI was also a secondary outcome measure in all 3 trials, and the studies were not primarily powered to detect changes in the NPI. This significant finding deserves further investigation as a primary outcome measure.
Memantine was not examined as monotherapy in any of the studies except for the DOMINO trial [21
]. Thus, certainty cannot be obtained from any of the other trials that show benefit of combination therapy, as none controlled for potential benefit from memantine alone.
In the blinded RCTs, there were significantly more dropouts from the control groups in the pooled analysis of all 3 trials and in the subgroup analysis of moderate to severe dementia, when the monotherapy arm from the DOMINO trial was memantine. Tariot et al. [13
] suggest that with more dropouts in the control group (OR 1.89; 95% CI 1.15–3.1), there is a possibility of underestimating the effect of memantine. Alternatively, a general argument can be made that better patient adherence is associated with better patient outcome [38
]. The 3 trials use LOCF in their ITT population, which is commonly used in dementia studies. This method has been challenged [39
] because it can lead to measurement bias, as the patients who drop out will have their last observation reported as their final outcome, leading the investigator to act on the assumption that the disease has stopped progressing, thus falsely overestimating the effect of a treatment arm or underestimating the effect of treatment if dropouts were more in the placebo arm. However, the results were not very different the OC analysis. The dropout rates were overall low in the remaining studies that reported it, and the medications appear to be well tolerated.
Limitations of this review include the need to convert SEs to SDs and the use of standard mean differences in calculating the effect size of cognitive and functional outcomes as each of the studies used separate or different versions of scales. There are few studies included in this review, and the paucity of literature in this area makes it difficult to come to a definite conclusion. Publication bias is possible, and we were not able to perform a funnel plot because of the low number of studies analyzed. The varying severity of AD in the patients included in the different studies and the different ChEIs used in one of the blinded RCTs also are limitations. Fortunately, analyzing moderate to severe cases only helped limit the ChEI analyzed to donepezil. Conversely, including all ChEI in the analysis has the benefit of identifying a drug class effect [18
Estimations provided by effect sizes are not optimal for describing MCID [40
], particularly with the pooling of performance from different scales. Therefore, prior to concluding, the issue of how meaningful these changes are must be examined. In other words, are these changes significant on a clinical level or do they merely represent changes in scores without really impacting the patient or family? Jaeschke et al. [41
] provided a definition for what is known as the MCID: ‘The smallest difference in score in the domain of interest which patients perceive as beneficial and which would mandate, in the absence of troublesome side effects and excessive cost, a change in the patient's management.’ Looking at each of the blinded RCTs, we find that Howard et al. [21
] is the only study that derived an MCID from their own population, while the other two used the CIBIC-Plus as an indicator of clinical impact, and only Tariot et al. [13
] showed a significant change in the CIBIC-Plus in favor of combination. The probability of the MCID also being different with differing AD severity levels has previously been raised [42
]. Burback et al. [42
] suggest that larger sample sizes and observing patients in trials for at least 1 year is required before being able to detect an MCID. In this review, only the DOMINO trial observed patients for 1 year.
A systematic review of ChEIs in comparison to placebo in AD patients found a mean change that was beneath the US Food and Drug Administration's consensus proposed MCID of 4, as measured by the ADAS-cog, ranging from 1.5 to 3.9 points [43
]. Despite this interesting finding, ChEIs are routinely used and appreciated; so, determining what exactly is an appropriate MCID remains elusive. It is likely to vary at a population level, if not at an individual level.
In summary, an effect was seen in moderate to severe AD patients; however, we believe that this finding should be interpreted cautiously, due to concerns about the weight of one of the studies and the fact that the MCID was not reached despite statistical significant improvement on a scale in another study. A recommendation to use combination therapy in the form of memantine in conjunction with a ChEI to reduce deterioration in cognition or function in patients with any type of dementia, including AD, cannot be made at this time. The significant effect sizes observed in this analysis suggest that further trials exploring combination therapy, particularly in moderate to severe AD, are warranted. Attributing the improvement seen in some studies of AD patients to combination therapy will require further blinded RCTs that replicate these results and have separate monotherapy arms of memantine and a ChEI. The definition of dementia type, as well as dementia severity, should also be clearly formulated. Trials should also consider using mixed models in their analysis that may yield less biased results than the OC or LOCF approaches [45
]. Combination therapy appears to be safe and well tolerated when compared to monotherapy. No conclusions can be made on the use of combination therapy in other forms of dementia at this time given the absence of adequate studies.
Other recommendations for future research would be assessing the response to combination therapy with a behavioral measure as the primary outcome. Investigating the response in patients with various comorbidities that are encountered commonly in the geriatric population such as diabetes, hypertension and hyperlipidemia, and exploring the influence of biomarkers, such APOE
4 status, cerebrospinal fluid tau and amyloid protein, and emerging neuroimaging techniques would also be rewarding. More trials researching response in other dementia types are also recommended.