by Reinhold Schmidt
In the June issue of the European Journal of Neurology, members of the Subspecialty Scientific Panel Dementia and Cognitive Disorders panel of the European Academy of Neurology publish a Guideline on concomitant use of cholinesterase inhibitors (ChEI) and memantine in moderate to severe Alzheimer’s disease (AD).
Clinical benefits of a combination of ChEI and memantine have been described in AD patients. Despite beneficial effects, the UK National Institute for Health and Care Excellence (NICE) did not consider the evidence sufficient to recommend the use of dual therapy in AD. The benefits of dual therapy reported in controlled trials was modest, but clinicians want to provide the most efficient treatment to their patients. Thus, the use of combination therapy instead of ChEI treatment alone in patients with moderate to severe AD has been an issue of debate ever since the unfavorable NICE decision. Importantly, prior to the current publication of the EAN Subspecialty Scientific Panel Dementia and Cognitive Disorders, there has been no clinical guideline on the use of combination therapy in AD for different clinical outcomes based on systematic assessment of quality of evidence. This was the rationale for the panel to produce such a guideline following the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group.
The GRADE approach was considered to be ideal as it is based on a sequential assessment of the quality of evidence, followed by assessment of the balance between advantages and disadvantages, and finally judgement about the strength of recommendations. Experts from 12 European countries were involved in this process and after systematic assessment of all available controlled trials consensus was reached by use of the Delphi method. The panel suggested that the use of a combination of ChEI plus memantine rather than ChEI alone may provide useful benefits in patients with moderate to severe AD. The observed treatment effects remained modest in terms of clinical management of individual patients. Thus, the overall strength of the recommendation was weak. The evidence for use of the combination for moderate to severe AD varied between the clinical outcomes. It should be noted that it was strong for patients with behavioural symptoms and that the recommendation for use of dual therapy in moderate to severe AD patients with behavioral symptoms was strong.
The authors of the guideline pointed out that the strong recommendation for behavioural symptoms was further emphasised by the fact that GRADE also includes costs as a determinant of the strength of recommendation, and that it is well established that behavioural symptoms in patients with AD are associated with higher care costs than in AD patients with no or little behavioural change.
Abstract:
Background and purpose: Previous studies have indicated clinical benefits of a combination of cholinesterase inhibitors (ChEI) and memantine over ChEI monotherapy in Alzheimer’s disease (AD). Our objective was the development of guidelines on the question of whether combined ChEI/memantine treatment rather than ChEI alone should be used in patients with moderate to severe AD to improve global clinical impression (GCI), cognition, behaviour and activities of daily living (ADL).
Methods: A systematic review and meta-analysis of randomized controlled trials based on a literature search in ALOIS, the register of the Cochrane Dementia and Cognitive Improvement Group, was carried out with subsequent guideline development according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system.
Results: Pooled data from four trials including 1549 AD patients in the moderate to severe disease stage demonstrated significant beneficial effects of combination therapy compared to ChEI monotherapy for GCI [standardized mean difference (SMD) −0.20; 95% confidence interval (CI) −0.31; −0.09], cognitive functioning (SMD −0.27, 95% CI −0.37; −0.17) and behaviour (SMD −0.19; 95% CI −0.31; −0.07). The quality of evidence was high for behaviour, moderate for cognitive function and GCI and low for ADL. Agreement of panellists was reached after the second round of the consensus finding procedure. The desirable effects of combined ChEI and memantine treatment were considered to outweigh undesirable effects. The evidence was weak for cognition, GCI and ADL so that the general recommendation for using combination therapy was weak.
Conclusions: We suggest the use of a combination of ChEI plus memantine rather than ChEI alone in patients with moderate to severe AD. The strength of this recommendation is weak.
