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Vitamin B and slowing the rate of Brain Atrophy: the numbers don't add up

Carl Heneghan
Last edited 14th September 2012

‘A new study suggests high doses of B vitamins may halve the rate of brain shrinkage in older people experiencing some of the warning signs of Alzheimer's disease.’ reports the BBC

A total of 168 participants (85 in active treatment group; 83 receiving placebo) completed the MRI section of the trial from 271. Therefore the study lost a lot of participants – where did they go?

The researchers state the efficacy analyses were performed on the basis of the intention-to-treat principle. But I have serious concerns that they were not.

The intenton -to-treat aims to avoid bias arising due to drop outs. For example, if people who had worse cognitive decline tend to drop out at a higher rate, even a completely ineffective treatment may appear to be providing benefits.

Thus if you just compare the primary outcome measure before and after the treatment for only those who finish the study (forgetting to count those enrolled originally, but subsequently excluded or not followed up) the results are likely to be misleading.

Thus everyone who begins the treatment, in this case Vitamin B, should be considered to be part of the trial and have the outcome assessed.

So what did they do in this study?
The main outcome in the study published in Plos One was rates of brain atrophy. The requirement was, subjects had both a baseline and a follow-up MRI, researchers state they conducted an intention-to-treat analysis for the main outcome in the subgroup that completed both MRI scans (n = 168).

What do you think? is this intention-to-treat?

Well, if you are like me, you will be thinking this invalidates the intention-to-treat principle. This seriously affects the ability to believe the results. This is a per protocol analysis and much more likely to lead to spurious findings.

If you look at the results for serious adverse events this was evaluated in the total intention-to-treat group (n = 266/271).

Although treatment with vit B after 24 months significantly slowed the rate of brain atrophy by 30% this is a relative measure. The absolute reduction is 0.32% over the length of the trial. The question is; is this clinically significance? Given adherence, was about 75% and 17/83 (21%) of the placebo group had taken supplementary folic acid or vitamin B12. In the active treatment group, and 14/ 84 (17%) in the treatment group did not take, or did not absorb, the vitamins, only 136 were defined as biologically compliant.

We seem to have lost half of the original group. I am feeling less convinced about the reuslts the more the numbers reduce – therefore the conclusions just don’t add up

I'd call this an interesting result. But what is needed is a much larger trial, with a well defined clinically significant outcome. Ideally this would be progression to Alzheimer’s disease.

Reply from authors of VITACOG paper

Dear Dr Heneghan and colleagues

We will start with what we agree on: This is an interesting result; and much larger trials are needed.

Then to your critical points. In a compact paper, it is often difficult to describe clearly what has been done; and the reader needs to look at the Supplementary material on the web as well as the main text.

Regarding the study population: The MRI population refers to a sub-study of the total population that volunteered to undergo scans. People were asked in advance before randomization whether they would accept to undergo 2 MRI scans. Out of the total 271 subjects that were randomized, only 187 agreed, or were able, to be part the MRI arm of the study. When we randomized, we took into account whether they had volunteered to participate in MRI or not (minimization for MRI consent). Of those 187 that underwent MRI at baseline, 180 completed the second scan, i.e., a mere 3.7 % drop out. However, not all scans were technically suitable for use. One example that renders an MRI scan of little value is if the patient moves during the acquisition. So out of all scans, we obtained 168 useful scan pairs (85 in the B vitamin group, 83 in the placebo group). However, even if we consider every subject lost to analyses as a drop out (true drop out due to disease etc + technical drop out), there was only a 10.2% drop-out over 2 y. This proportion is not unusual in trials with elderly people.

Intention-to-treat: We agree that the ITT principle is to avoid bias related to drop out, but that is only one bias that ITT tries to avoid. It is also used to avoid bias due to poor compliance with the study protocol. ITT simply states that you include all randomized participants that potentially can be included in the statistical analyses, independent of what has happened with the participant after randomization, and independent of whether the participant followed the protocol.
We have sought advice from several people on this particular issue. Since rate of atrophy requires both a base-line and follow-up scan, the ITT population must be limited to those with both scans. Imputation of follow-up scan data cannot be advised on this occasion. If you disagree, then we will have to agree to disagree on this particular point.
So for this particular trial, ITT means that we did not take into consideration whether subjects were compliant in terms of taking the assigned tablets, or if they started taking B vitamin supplements, or if they otherwise did not adhere to protocol.

Relative risk reduction: Finally, you raise the point of relative risk reduction in rate of atrophy, and whether the observed changes are clinically relevant. The average brain volume in our subjects was about 1380 mL at baseline. In the placebo group, atrophy rate was 1.08 %, corresponding to a loss of 15 mL brain tissue per year. B vitamin treatment reduced that to 0.76% (about 10 ml per year). In normal ageing, one expects about 0.5% loss per year, or 7 mL per year, compared to a staggering 2.5% (35 mL) in Alzheimer’s disease). We believe that the B vitamin effect in mild cognitive impairment is biologically relevant. Furthermore, the critical question is not only how much brain tissue is lost, but where the brain tissue is lost!
We observed in our trial that apart from the baseline cognitive score, the rate of atrophy was the most important determinant of cognitive decline in people with Mild Cognitive Impairment.

We are now analyzing the changes in cognitive test data in the whole VITACOG trial cohort. We have reported at the Alzheimer's Association International Conference on Alzheimer's Disease that B vitamin treatment slows the decline in a memory test (delayed recall) compared with placebo in the group with elevated homocysteine concentrations.

We are now performing further statistical analyses with the other cognitive tests as outcome variables. The results will hopefully be published soon.

We believe that our findings are promising and should initiate larger trials and with cognitive and clinical endpoints.

David Smith and Helga Refsum

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