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Simvastatin in acute optic neuritis

Dear Editor We read with interest the paper ‘Simvastatin improves final visual outcome in acute optic neuritis: a randomized study’,1 by Tsakiri et al., which investigated the suggestion by several small studies2-5 that simvastatin is neuroprotective in optic neuritis. Tsakiri and colleagues used a small (64 subjects), single-center, randomized, prospective phase 2 proof of concept study to examine whether simvastatin is neuroprotective in acute optic neuritis (AON). Although their primary research question (contrast sensitivity) gave non-significant results, the authors concluded that simvastatin is possibly effective because visual evoked potential (VEP) parameters showed significant improvement in the simvastatin group compared with the placebo group. Simvastatin is readily available in most countries for the treatment of high cholesterol, so it is important to clarify that this study did not provide evidence for a neuroprotective effect for simvastatin in AON. A common and important problem in smaller clinical trials is that randomization does not guarantee adequate balancing of key parameters. This was the case for VEP data in this study: the values for VEP latency and amplitude at baseline were worse for the placebo than for the simvastatin groups (see Figure 2 in their paper). In fact, the mean difference between the placebo and simvastatin arms on days 0 and 14 in VEP latency (15–26 ms) was similar to the mean difference on days 90 and 180 (20–22 ms) during the treatment period. As shown in Figure 2 of their paper, the simvastatin and placebo VEP latency curves are almost superimposable after vertical displacement to equate baseline values. Another problem with the VEP analyses is that the authors were not able to record a VEP on the affected eye in nearly 40% of the subjects (24 of 64). For these subjects, the authors arbitrarily assigned the VEP latency to ‘250 ms’. We believe this is inappropriate and likely contributed to the appearance of a treatment effect as it amplified the effects of unbalanced randomization. A sensitivity analysis excluding these 24 subjects, or an alternative analysis that assigned the median VEP group latency (around 170 ms), would have been better ways of addressing the missing data. One option for subjects with a first episode of AON is to use change over time in the affected eye relative to the unaffected fellow eye. This may be a viable option for this study because nearly 90% of subjects did not have multiple sclerosis (MS). For studies in which the fellow eye is likely affected, as in AON in MS patients, it may be more appropriate to compare data collected at 3–4 weeks post ON onset with measures obtained at later time points in the same eye to determine efficacy of treatment. This strategy would minimize the effects of early optic nerve swelling on the data. Reliance on randomization to negate bias is a fallacy to which many clinical trials fall victim. Important differences in group composition need to be controlled, not randomized; severity at baseline is surely one of these differences. Discovery of an unexpected and important baseline discrepancy in the study groups after the conclusion of the study requires addressing the potential implications of the discrepancy on the observed results.