Cerebrolysin for vascular dementia: how much evidence is enough?

In this blog designed for a scientific audience we will look at a putative treatment for vascular dementia called Cerebrolysin.  Martin Taylor-Rowan (MTR) and Bogna Drozdowska (BD), two researchers working in the field of vascular dementia, will interpret the clinical significance of the existing data.  Martin and Bogna have differing views on the topic, so Terry Quinn (TQ – co-ordinating editor Cochrane Dementia) will ‘referee’ and give some opening and closing thoughts.

TQ: Vascular dementia (VaD) is the second commonest cause of dementia and increasingly we are recognising that many dementias are ‘mixed’, with a vascular component in addition to other pathologies. Despite its importance, vascular dementia is poorly understood, with limited research and limited therapeutic options. So I was very interested to see that within the Cochrane Dementia group’s library we had a ‘positive’ review of a pharmacological treatment for vascular dementia. The intervention in question is ‘Cerebrolysin’.  Cerebrolysin is a mixture of compounds derived from pig brain tissue that is given as daily injections over several weeks. While it is not well known in UK (I had to look it up) it is commonly used in Russia, Eastern Europe and China. I asked two researchers with an interest in vascular dementia to assess the Cochrane review. It all got a bit heated.

Adult Daughter Talking To Father At Home

Cerebrolysin for vascular dementia: what does the evidence say?

First lets hear the ‘case against’, from Martin:

MTR: The Cochrane review of Cerebrolysin is high quality, however the included studies are not. I accept that most of the studies included in the review report beneficial changes in cognition. However, the available studies are limited in number and have potential biases. Do small trials of very selected populations have relevance to the majority of people living with vascular dementia in the UK? It seems odd to me that a treatment that has international traction has such a modest evidence base. Statistical assessment of publication bias was not possible in the Cochrane review and I wonder if selective publication of positive results could be a factor here.

The effects of cerobrolysin as a treatment for VaD may be consistent, but it is not clear that the effects reported are important, or even biologically plausible. Do we really believe that pig brain injections will cure dementia? Improvements to performance on detailed cognitive assessments are meaningless if they do not translate to benefits in everyday functioning. Only two studies assessed function; one found a positive effect, the other found no effect. There is no evidence of any improvement to quality of life or reduced care-giver burden yet these are key aims of any dementia treatment. The follow-up duration for these studies covered only the short-term; hence there is no evidence of any long-term benefit or, for that matter, side-effects.  In addition to unintended side effects, we should consider the inherent burden associated with this invasive, time-consuming and presumably expensive treatment.  For the very modest, possible, short-term effects on cognition, we have to ask, is it really worth it?

senior man shaving

Improvements in cognitive assessments are meaningless if they don’t translate into benefits in everyday functioning

TQ: Strong words from Martin, Bogna over to you:

BD: Even a small improvement in cognition can make a great difference to a person suffering from vascular dementia and their carer. I believe that Cerebrolysin has the potential to do that. The results of analyses presented in the Cochrane review demonstrate superiority of Cerebrolysin over placebo for many important measures. This included improving outcomes on measures of global cognition, specific cognitive functions and global clinical assessment. This consistency of effect across studies and across outcomes is compelling. At the same time as showing cognitive improvements, no adverse effects were found with the treatment.

The Cochrane review suggests benefit of Cerebrolysin and I see no reason to disagree with this conclusion. The review was high quality, the search was comprehensive including foreign language publications and quality assessment was thorough. Only one study was rated as being at risk of bias and sensitivity analysis showed that omitting this trial would not have altered the obtained results.

Cerebrolysin is used in many countries with no obvious signals of harm. The potential beneficial effects are aligned with results of pre-clinical and laboratory studies that suggest a neurorestorative effect of Cerebrolysin. Since the traditional western medicine research pipeline has failed to produce disease modifying treatments for dementia, why are we so quick to dismiss this potentially safe and efficacious treatment? Although the available evidence is not yet sufficient to recommend Cerebrolysin as routine medical practice, available data should encourage researchers and funding bodies to engage in large scale, long-term trials. Particularly as at present there is no evidence for a better pharmacological alternative.

Scientist using microscope in laboratory: cerebrolysin for dementia

Available data on cerebrolysin for vascular dementia should encourage researchers to engage in large-scale trials

TQ: There are some good arguments from both sides. When faced with a progressive neurodegenerative condition such as vascular dementia, any signal of a potential treatment is welcome, but we should not lower the threshold of evidence required to inform our prescribing decisions. The available data are limited and there are issues with internal and external validity. It is interesting to note that the recent Cochrane Stroke Group review of Cerebrolysin for ischaemic stroke, a condition closely related to vascular dementia, found no efficacy and reported concerning signals around safety. I think both Martin and Bogna would agree that the available evidence is interesting but far from definitive. We need more studies and these studies must be sufficiently large and robust to answer questions about safety and efficacy. In the broader sense we desperately need more research around vascular dementia pathogenesis, prevention and treatment.

Join in the conversation on Twitter with @DrTerryQuinn @CochraneUK @CochraneDCIG #dementiaspotlight or leave a comment on the blog.

References may be found here.

Terry Quinn, Martin Taylor-Rowan and Bogna Drozdowska have nothing to disclose. Author biographies may be viewed by clicking their names in the by-line.

 

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Terry Quinn

About Terry Quinn

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Dr Terry Quinn is Stroke Association / Chief Scientist Office Senior Clinical Lecturer based in the Institute of Cardiovascular and Medical Sciences, University of Glasgow. Terry has a broad research portfolio, his principal research interests are trial methodology, functional/cognitive assessment and neuropsychological consequences of cardiovascular disease. Recent notable outputs include co-authoring best practice guidance for test accuracy studies in dementia; creating online training for stroke trials and developing short form assessment scales. Terry has published extensively on stroke, cognition and test accuracy. He is Principal Investigator for a number of studies and holds a program grant to look at cognitive outcomes following stroke. Terry has editorial board positions with PLOS, Frontiers and Stroke , including coordinating editor of the Cochrane Dementia Group. He is part of the NIHR Complex Reviews Support Group and is founder and co-chair of the Scottish Care-Home Research Group. Terry’s work has always maintained a clinical focus and he combines research activity with teaching and clinical commitments in the wards of Glasgow Royal Infirmary. Email: terry.quinn@glasgow.ac.uk Twitter: @DrTerryQuinn URL: http://www.gla.ac.uk/researchinstitutes/icams/staff/terryquinn/

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