Finally, expected treatment-related benefits must be balanced with potential treatment-related risks to provide an informed picture of the risk-benefit calculus of the treatment paradigm to patients and caregivers; this study presents the largest safety and AE data profile specifically available inhibitor order us for the combination of memantine added to donepezil in moderate, as well as for moderate to severe AD. Limitations of study Only two 24-week phase III RCTs met inclusion criteria and could thus be included, and only a subgroup of the patients from each study was included, for the reasons discussed. Also, while the MMSE has been commonly used as a disease stage proxy to determine patient inclusion in clinical trials, it only measures cognition, which is just one of several AD symptom domains, and it does so in a very limited way.

The present study used MMSE in the same manner, and is thus subject to these same limitations. However, this does allow application of these results to the same criteria and populations identified by funding groups or agencies that provide treatment guidelines for the use or reimbursement of AD medications. Furthermore, measuring marked clinical worsening as defined in this study, may not capture significant decline in all patients, as a patient may largely deteriorate in one domain and yet not be considered to have marked clinical worsening; it is therefore a conservative estimate [6].

Finally, limiting data inclusion criteria in this study to test an a priori hypothesis leverages patient homogeneity, and likely lowers the odds of variability in study measures, thereby increasing the internal validity of the results, but at the cost of potentially decreasing external validity and generalisability of results to the wider and more heterogeneous non-research AD patient population; particularly the generalisability of results to those patients who are in milder clinical stages, are treated with ChEIs other than donepezil (that is, patients treated with galantamine or rivastigmine), or are enrolled in primarily non-research clinical settings. Drug_discovery In clinical practice, patients are also often treated for much longer than the limited 24-week duration studied in these phase III RCTs. This has been emphasised to argue that Level II grade evidence from long-term observational clinical cohort studies should be used to complement and inform clinicians and researchers in the process of therapeutic discovery CHIR99021 and assessment, as well as in determining and monitoring the long-term risk-benefit calculus of therapies to patients and to society [34]. Conclusions The addition of memantine to patients’ ChEI therapy when they reach the moderate stage of AD has important practical relevance.