intention to treat
Vitamin B and slowing the rate of Brain Atrophy: the numbers don't add up
‘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.