Review: Systematic Review of Safety and Tolerability of Donepezil, Rivastigmine and Galantamine

The paper reviewed here is ‘Safety and Tolerability of Donepezil, Rivastigmine and Galantamine for patients with Alzheimer’s Disease: Systematic Review of the ‘Real-World’ Evidence’ by Lockhart and colleagues and freely available here.

Aim: The aim of the study is clearly outlined and reflected in the title.

Method: The authors identify trials from the following sources

  • Medline database
  • Cochrane library

The researchers used the following search terms in MESH and the text of the abstract: Dementia, Alzheimer’s disease, Donepezil, Rivastigmine, Galantamine, cohort, retrospective, naturalistic. The researchers also hand-searched a number of conference proceedings. Primary outcome measures were

  • Incidence of individual AE’s reported
  • Withdrawal due to AE’s
  • Incidence of individual AE’s

The researchers opted for a qualitative analysis rather than a meta-analysis ‘due to potential heterogeneity in included studies’.

Study designs were assessed using the Newcastle-Ottawa Scale which is

designed to appraise the methodological quality of comparative cohort and case control studies

The researchers include a detailed list of inclusion and exclusion criteria in table 1. The impression I got from reading the criteria is that the diagnostic criteria, trial type (essentially randomised trials) and of course treatment were the most significant factors influencing inclusion. Thereafter the inclusion criteria were fairly broad meaning that there was an opportunity to include a relatively large number of papers.

Results: There were a number of steps involved in reaching the final number of 12 papers and the interested reader is referred to the original paper linked to above. The characteristics of the 12 studies are summarised in Table 2. In the identified studies, the numbers for the different acetylcholinesterase inhibitors were

Donepezil: Retrospective analysis – n=6294; Prospective analysis n=4034

Rivastigmine: Retrospective analysis n=1842; Prospective analysis n=2143

Galantamine: Retrospective analysis n=809; Prospective analysis n=418

Table 3 shows withdrawal from the medication to GI effects. There is a wide spread within the prospective study – withdrawal due to any GI AE category although the difference in sample sizes cause difficulties in interpretation. In a number of cases p values are given. I might have missed this, but I couldn’t identify what tests were being used to produce the p-values.

Table 4 shows withdrawal due to all non-GI adverse events. My impression from inspecting this table was that there was a broad range across the studies – both retrospective and prospective and this wasn’t summarised with mean and confidence intervals for aggregated data. Looking through the data further, the figures for withdrawal due to cardiovascular events ranged from 0 to 1.2%.

Table 5 shows an aggregation of GI and non-GI adverse events and here there are a number of consistent findings across various studies particularly in the GI studies although there are outliers in the dataset. Again the data is not pooled although this is explained in the methodology section.

Table 6 shows CNS adverse events. There were a lot of categories here but there were a relatively small number of data points for each category.

Table 7 shows ‘non-CNS-related AE’s’ which covers a number of cardiac and miscellaneous AE’s (excluding GI (with the exception of weight loss)). The De La Gastine study shows a higher incidence of cardiac arrythmias for the different ACHEI’s but has smaller sample sizes than the other studies. Here again I thought the use of confidence intervals and statistical comparison between groups would be helpful.

Conflict of Interest: I couldn’t identify a COI declaration and the authors identify their institutions as Pfizer and Abacus International, a health consultancy firm.

Conclusions: I thought the researchers had gathered a large amount of useful data. It would have been interesting to see the information displayed with the use of confidence intervals and for these to be used in a between-group comparison. Even a lack of difference between groups in itself would have been interesting and I thought would have been helpful in drawing firm conclusions. The researchers discuss why they have opted for a qualitative analysis.

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