Reply

We have read the commentary by Tariot et al. [1] with interest and are delighted that our paper has provoked additional discussion. With regard to the presentation of the multiple metagraphs, our method of labeling did not include the term ‘favors'. In figure 5 for example, the labels along the x-axis are either ‘control' or ‘experimental', unlike the new figure provided by Tariot et al., where the word ‘favors' precedes each term. This word was omitted from the graphs in order to avoid indicating that there was any favorable response towards a particular group. The graph instead indicates that the control group showed higher Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) values, and this was correctly interpreted in our discussion [2] as a nonsignificant trend to favor combination therapy. A revised graph now contains a clarification in the legend (fig. 4). The confidence interval plots and labels were set to be consistent throughout the paper for better appreciation of the results between the various assessments used. The observation regarding the standard deviation value is valid and a correction has been made. The corrected p value however still does not reach statistical significance (<0.05) after this adjustment. Lastly, we closely inspected the remaining calculations and found similar deviations involving values obtained from the study by Tariot et al. [3], and these have also been corrected (fig. 1, 2, 3, 4). While these corrections do not lead to a change in the paper's final conclusions or recommendations, it shows that in the patients in the mild-to-severe group of Alzheimer's disease (AD), combination therapy does not reveal any benefit in cognitive, behavioral or functional assessments. The authors regret this error and are thankful to Tariot et al. [1] for contributing to the accuracy of the study. In our approach, we chose to include all levels of dementia severity in a single analysis as a first step. In addition to the explanation provided in the discussion section of the article [2] and the concern about heterogeneity that might result from the inclusion of all severity levels in the analysis, we add that our systematic review assessed many study types such as cohorts and open-label studies, some of which did use combination therapy in mild-to-moderate cases. As their results were not suitable for meta-analyses, it became necessary to analyze randomized controlled trials that included mild-to-severe cases. However, due to the broad clinical spectrum and the high I2 scores obtained, it is more important to look at the subgroup analyses. A recent notable study also assessed mild-to-moderate AD patients that were already on cholinesterase inhibitor (ChEI). Patients were randomized to vitamin E, memantine or the two treatments in combination, and the results showed that only the vitamin E arm had slower functional decline compared with the placebo group (ChEI therapy) [4].The noteworthy meta-analysis by Atri et al. [5] mentioned in the commentary assessed patients with moderate-to-severe AD, and among the methodological differences was the inclusion of patients only on donepezil as a ChEI and the exclusion of those on <10 mg/day. Our study's goal was to assess for a class effect arising from ChEI or memantine and, if enough studies were available, to conduct subgroup analyses with each individual ChEI. Despite the differences, both studies find a statistically significant effect in cognition and functional outcome in the moderate-to-severe groups, favoring combination therapy. A separate study included data from Tariot et al. [3], Porsteinsson et al. [6], and a third unpublished trial MEM-MD-50 [7] in a meta-analysis of moderate-to-severe cases of AD. While the authors also found statistical significance in favor of a combination therapy on cognition, the study similarly came to the conclusion that more evidence was required [8]. While there were limitations in the study by Howard et al. [9] and a concern about the longer follow-up duration, the study provided a comparison of combination therapy with a memantine monotherapy arm. Thus, it helped in determining which treatment arm the benefits can be attributed to and was also in line with our a priori research objective. Even though the I2 scores were low in the moderate-to-severe subgroup analyses, this does not exclude clinical or methodological heterogeneity. Including the study by Howard et al. in the meta-analysis was helpful, since patients are not treated for only 24 weeks in clinical practice. Given the broad spectrum from mild-to-severe stages of AD when donepezil can be used, it is likely that clinicians encounter patients who have been treated for much longer periods of time. Analyzing the two studies together provided us with a broader answer about the potential application of combination therapy; starting with a more generalized comparison followed by subgroup analyses to explore the causes of heterogeneity is an advantageous strategy [10] when conducting meta-analyses. Further subgroup analysis based on the duration of therapy was not done due to the small number of studies, which is a main reason for our conservative recommendation.All these issues were taken into account when we drew our initial conclusions. Although there is no strong evidence against combining ChEI with memantine, we would like to take this opportunity to reiterate that original research exploring combination therapy is still required before confident recommendations can be made.

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