05. Are AchE inhibitors effective?

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Today, we’ll look at a new meta-analysis of the efficacy of acetylcholinesterase inhibitors in the treatment of dementia. This is a new study from Ruth Knight and colleagues in the UK published in the *Journal of Dementia* in May 2018. They included patients with Parkinson’s with Lewy bodies—so, patients developing dementia in the context of Parkinson’s. This is looking at dementia across the board, not just Alzheimer’s, and looking at the effect of these acetylcholinesterase inhibitors.

Interestingly, at 6 months, the donepezil effect is clearly better than placebo. It’s not a big surprise, but it’s nice to see that effect size come through strong. Measurement system was Mini-Mental Status Exam or, where available, the ADAS-Cog—the Cognitive subscale of the Alzheimer’s Disease Assessment Scale. Dr. Knight and colleagues found fewer studies that went out to 1 year, but in those that were available, the effect of donepezil versus placebo was still there and interestingly not so for memantine, although there were far fewer studies available for memantine than for donepezil. I think maybe most importantly in this meta-analysis, the donepezil effect was twice as large for patients with Parkinson’s-associated dementia. So, this means there was a strong effect of the acetylcholinesterase inhibitor in Parkinson’s dementia with Lewy bodies.

Now, although this is a meta-analysis, the data don’t extend past 1 year at the most. They are multiple studies lumped together, but none of them extend beyond a year. That means for the longer-term effect, we’re still, to my knowledge, working from open-label extension studies from the manufacturer’s original trials. That means the trial was done versus placebo, and then at the endpoint, either 6 months or 1 year, patients stayed on and were followed (some of them, not all of them) to see how they were doing farther down the road. One example would be Rogers et al. from 2000. And the graph from those studies, to me, is the key to this whole issue. And you may already be familiar with this finding. Compared to a steady decline in cognitive ability in the placebo groups and in patients who were not treated with acetylcholinesterase inhibitors, the donepezil curve is flat. It does not show that decline for about 6 to 9 months, but then the slope of that curve in cognitive decline resumes a downward trend roughly parallel to the untreated group. I’m trying to draw a graph for you here. Imagine 2 lines in parallel, and at the top of the donepezil curve, there is a flat section that pushes it out in time. Then the curves are parallel. In other words, there is a decline in cognitive function with donepezil. It’s very much like decline in function without donepezil. You buy 6 to 9 months of cognitive function.

So, the question then, clinically, is: How worth it to the patient and his or her family are those 6 to 9 months? Because I have never seen a study of this, but I understand that if you were to stop the donepezil or other acetylcholinesterase inhibitors after 6 to 9 months, you actually fall back down to the untreated curve. You have to stay on it if you’re going to maintain the benefit. That means we’re really looking at buying 6 to 9 months of preservation of cognitive function at the expense of potential for side effects and having to add this medication to whatever else the patient is taking for the rest of his or her life. That’s a tricky decision.

In summary, this new meta-analysis confirms a benefit for donepezil and not for memantine at least at 1 year. And fundamentally, it doesn’t really change the equation that clinicians manage, which is comparing risks and benefits for that 6- to 9-month preservation of cognitive function.

Abstract

A Systematic Review and Meta-Analysis of the Effectiveness of Acetylcholinesterase Inhibitors and Memantine in Treating the Cognitive Symptoms of Dementia

Knight R., Khondoker M., Magill N., Stewart R., Landau S.

Background: Acetylcholinesterase inhibitors (AChEIs) and memantine are commonly used in the management of dementia. In routine clinical practice, dementia is often monitored via the Mini-Mental State Examination (MMSE). We conducted a systematic review and meta-analysis of the effects of these drugs on MMSE scores.

Summary: Eighty trials were identified. Pooled effect estimates were in favour of both AChEIs and memantine at 6 months. Meta-regression indicated that dementia subtype was a moderator of AChEI treatment effect, with the effect of treatment versus control twice as high for patients with Parkinson disease dementia/ dementia with Lewy bodies (2.11 MMSE points at 6 months) as for patients with Alzheimer disease/vascular dementia (0.91 MMSE points at 6 months).

Key Messages: AChEIs demonstrate a modest effect versus control on MMSE scores which is moderated by dementia subtype. For memantine the effect is smaller.

Reference

Knight, R., Khondoker, M., Magill, N., Stewart, R., & Landau, S. (2018). A systematic review and meta-analysis of the effectiveness of Acetylcholinesterase inhibitors and Memantine in treating the cognitive symptoms of dementia. Dementia and Geriatric Cognitive Disorders, 45(3-4), 131-151.