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Meta-analyses Comparing Topical Treatments for Tinea Pedis
statistically significant (p=0.804). The lower bound of the 95% CI is Discussion
-47.2%, less than -10%, and therefore statistical non-inferiority cannot After an exhaustive review of the literature from the last four
be claimed. decades, it appears that very few high-quality vehicle-controlled
studies of topical treatments for tinea pedis have been published.
Clotrimazole The two comparative studies of a single application of terbinafine
The indirect comparison between terbinafine 1% FFS and clotrimazole 1% FFS versus vehicle are recent and particularly well-powered,
1% results in an effect of 24.1±6.8% to the advantage of terbinafine 1% with adequate sample sizes. Hence, results based on them are
FFS. This effect is clinically relevant (>10% and even 15%) and likely to be reliable. In contrast, many comparative studies of other
statistically significant (p<0.001). Therefore, superiority of a single topical treatments versus a vehicle are not recent and some of
application of terbinafine 1% FFS over clotrimazole 1% can be claimed. them had particularly small sample sizes. The chosen end-point of
mycological cure (defined as negative microscopy and negative
Tioconazole culture) must be interpreted carefully. The meta-analysis uses
The indirect comparison between terbinafine 1% FFS and tioconazole mycological cure six weeks post-treatment where available, but
1% cream results in an effect of -3.2±11.1% to the disadvantage of uses the last available data where six-week data are not reported.
terbinafine 1% FFS. This effect is clinically insignificant (<10%) and not If last available data are derived from samples collected too soon
statistically significant (p=0.773). The lower bound of the 95% CI after the end of therapy, there is a high likelihood of false-negative
(-25.0%) is less than -10%, and therefore statistical non-inferiority cultures (and hence false ‘cures’) as a negative culture
cannot be claimed. The size of the 95% CI is mainly explained by the immediately following therapy can be due to drug carry-over in the
low number of studies involved in this indirect comparison. sample, for example.
Oxiconazole It should be recalled that the mycological cure rates were not
The indirect comparison between terbinafine 1% FFS and oxiconazole assessed in a few publications as strictly defined in the meta-
1% cream results in an effect of 15.8±6.9% to the advantage of analysis. In these studies, microscopy and fungal culture results
terbinafine 1% FFS. This effect is clinically significant (greater than were reported independently and were not linked on a ‘by patient’
10%) and statistically significant (p=0.017). Therefore, the statistical basis. Therefore, if the two rates differed there is no means of
superiority of a single terbinafine 1% FFS over oxiconazole 1% cream knowing how many patients had both negative microscopy and
can be claimed. negative culture, and therefore how many truly experienced
‘mycological cure’ as defined for the meta-analysis. In these cases,
The Azoles as a Group the mycological cure rate is defined by convention in this report
The indirect comparison between terbinafine 1% FFS and azoles as a with reference to the lower of the two rates.
group results in an effect of 9.0±7.0% to the advantage of terbinafine
1% FFS. This effect tends towards clinical relevance (close to 10%), but This convention may overestimate the mycological cure rate within
is not statistically significant (p=0.201). However, non-inferiority of a each group (comparator and vehicle), but the resulting bias on the
single application of terbinafine 1% FFS over azoles can be claimed as difference in mycological cure rate between comparator and
the lower bound of the 95% CI (-4.8%) is greater than -10%. vehicle is likely to be moderate. Results derived from meta-
analyses and indirect comparisons are subject to inherent possible
Ciclopiroxolamine biases that cannot be quantified. However, it should be
The indirect comparison between terbinafine 1% FFS and emphasised that whereas all eligible studies evaluating terbinafine
ciclopiroxolamine results in an effect of 13.2±20.2% to the advantage 1% (FFS and other formulations) were included in the meta-
of terbinafine 1% FFS. This effect is not statistically significant analyses, negative or less favourable trials assessing other topical
(p=0.513). From a descriptive perspective, terbinafine 1% FFS can be drugs may not have been published, possibly leading to a positive
considered to be superior to ciclopiroxolamine. However, superiority bias to the advantage of these comparators in the indirect
of a single application of terbinafine 1% FFS to ciclopiroxolamine comparisons with terbinafine 1% FFS.
cannot be claimed statistically because the lower bound of the 95%
CI (-26.4%) is less than -10%. Note that the large 95% CI reflects It is noteworthy that the mycological cure rates observed in the
uncertainty about the true effect, which is explained by the vehicle-treated groups are consistent over time and across studies,
substantial heterogeneity of the treatment effects across studies. which strengthens the validity of indirect comparisons between a
single terbinafine 1% FFS and corresponding comparators.
Safety Data
Safety data were not uniformly reported in all publications. Some Conclusion
reported none at all, some reported adverse events in great detail and As with all meta-analyses, the results presented here should be
in the majority, which fell between these two extremes, the approach interpreted with some caution, but these indirect comparisons
taken to reporting side effects was not uniform. Table 3 shows a represent the best possible approach to the collective assessment
summary of the safety data from each publication. As would be of topical treatments for tinea pedis.
expected from commercially available topical antifungal treatments,
all products and formulations were well tolerated. Adverse effects Within these limitations, the current meta-analysis confirms the
occurred at a similar frequency in active and vehicle groups. Adverse findings of Korting et al.
1
that a single application of terbinafine FFS
events related to treatment were uncommon and comprised mostly is non-inferior to other formulations of terbinafine used in multiple
mild local effects such as itching or stinging, which did not usually applications (typically one or two daily applications for one week) for
require the treatment to be stopped. the treatment of interdigital tinea pedis. Moreover, our analysis
EUROPEAN DERMATOLOGY 25
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