Strengths and limitations:
This is the first well-designed trial robustly investigating the
hypothesis that folic acid could ameliorate hot flushes in
postmenopausal women. The standard therapeutic dose of 5mg was used. The
study screening criteria were precise and ensured that a carefully
characterised group of women with normal folate levels were included.
Randomisation and study conduct were according to a protocol using
double-blinding methods of concealment and computerised randomisation.
Drop-out rate was lower than expected and the study included a
modified-intention-to-treat sensitivity analysis.
The trial demonstrated that folic acid was safe and well-tolerated. In
contrast to HRT, literatures reported no concerns about safety of folic
acid and daily oral supplement of up to 10 mg folic acid rarely caused
side effects in healthy individuals. A few cases of allergic reactions
were.37, 38 A meta-analysis, including 13 RCTs with
49621 participants that compared folic acid versus placebo, found
no change in overall and site-specific cancer incidence when folic acid
supplementation was used at doses higher than those from fortification
for average duration of 5.2 years.39
We acknowledge that no formal measure was taken to address the issue of
multiple testing in the secondary outcome measures. The sample size used
in the study assumed a within-group standard deviation of 7.1 for the
change from baseline, but we observed greater variability with a
standard deviation greater than this in both treatment groups. This
combined with observing a smaller difference than anticipated, has
resulted in the study being underpowered to detect the clinically
relevant difference specified in the design. The planned sensitivity
analysis increased the patient population for the primary outcome by a
further 15 women. As a result, the analysis showed a trend towards a
statistically significant result for the unadjusted (p =0.099) and
adjusted (p =0.071) analyses. The overall treatment effect over
time from the multilevel mixed-effects model was not statistically
significant (p= 0.614). We also considered the treatment
effect in women with high frequency of hot flushes at baseline using a
cut-off of 72 which is the median number of hot flushes. The treatment
effect was -4.62 (-10.66, 1.42) and -0.50 (-3.20, 2.21) in the
>72 group and ≤72 group, respectively.