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Meta-analyses Comparing Topical Treatments for Tinea Pedis
The studies with clotrimazole gave more consistent results and the 1% cream, solution or gel. The lack of precision, partially explained by
difference from vehicle in mycological cure rates was 29.4±5.2% the low number of trials and the heterogeneity of treatment effect
(95% CI 19.3–39.6%). Only one vehicle-controlled study satisfying sizes among studies, is reflected in the length of the CI of the overall
the inclusion criteria was found for econazole, and the difference treatment effect. Therefore, the lower bound of the 95% CI (-18.2%) is
from vehicle in mycological cure rate was 49.6±8.2% (95% CI less than -10%, and statistical non-inferiority cannot be claimed.
33.5%–65.8%). The treatment effect was inconsistent across the two
vehicle-controlled studies with miconazole, and the meta-analysis Other Topically Active Allylamines
provided an overall difference from vehicle in mycological cure rates Butenafine and Naftifine
of 58.8±20.9% (95% CI 17.8–99.8%). Only one suitable vehicle- The indirect comparison between terbinafine 1% FFS and butenafine 1%
controlled study was found for tioconazole, in which the difference results in an effect of 8.7±9.6% to the advantage of terbinafine
from vehicle in mycological cure rate was 56.7±10.2% (95% CI FFS 1%. This effect is not statistically significant (p=0.363) or clinically
36.7–76.7%). With oxiconazole, there was no evidence of significant relevant (<10%). Terbinafine 1% FFS can be considered statistically non-
heterogeneity between the two available vehicle-controlled studies, inferior to butenafine 1% cream: the lower bound of the CI (-10.1%) is
and the overall difference from vehicle in mycological cure rates was very close to -10%. When excluding the Klaschka study, which included
37.7±5.3% (95% CI 27.4–48.1%). patients with an interdigital infection other than tinea pedis, the indirect
comparison between terbinafine 1% FFS and naftifine 1% gel or cream
When the studies with all of the azoles were analysed as a group, the results in an effect of 6.6±6.4% to the advantage of terbinafine 1% FFS.
overall difference from vehicle in mycological cure rates from Smith
26
This difference is not statistically significant (p=0.305) or clinically
(67.6±10.0%) and Ortiz
29
(78.0±6.2%) contributed significant relevant (<10%). Terbinafine 1% FFS can be considered non-inferior to
heterogeneity. However, unlike the Klaschka study with naftifine, the naftifine 1% gel or cream: the lower bound of the 95% CI (-6.0%) is
Smith and Ortiz studies (with bifonazole and miconazole, respectively), greater than -10%, and statistical non-inferiority can be claimed. When
although heterogenous with respect to the azoles group, did not including the Klaschka trial, the indirect comparison between terbinafine
contain any particular flaws that would justify their exclusion. 1% FFS and naftifine 1% gel or cream results in an effect of -2.1±13.5%
Therefore, they are included in the meta-analyses. This is a conservative to the disadvantage of terbinafine 1% FFS. This difference is not
approach for the indirect comparison with terbinafine FFS, as it gives statistically significant (p=0.877) or clinically relevant (<10%). The lack of
rise to a larger difference from vehicle in the azole group than would be precision is caused mainly by the heterogeneity of treatment effect sizes
the case if these two studies were excluded. The meta-analysis (with among studies, explained itself by the Klaschka study. The lower bound
the Smith and Ortiz studies included) provided an overall difference of the 95% CI (-28.6%) is less than -10%, and statistical non-inferiority
from vehicle in mycological cure rates for this group of 44.5±5.5% (95% cannot be claimed anymore.
CI 33.7–55.2%). These results are illustrated in Figure 1.
When excluding the Klaschka study, the indirect comparison between
Ciclopiroxolamine a single terbinafine 1% FFS and naftifine 1% or butenafine 1% results
The three studies with ciclopiroxolamine gave rather inconsistent in an effect of 7.7±5.9% to the advantage of terbinafine 1% FFS. From
results and the meta-analysis gave a difference from vehicle in a descriptive viewpoint, this difference is not statistically significant
mycological cure rates of 40.3±19.7% (95% CI 1.7–78.9%). These data (p=0.195) or clinically relevant (<10%). A single application of
are illustrated in Figure 1. terbinafine 1% FFS can be considered to be non-inferior to naftifine 1%
or butenafine 1%: the lower bound of the 95% CI (-4.0%) is greater than
Indirect Comparison Between Terbinafine -10% and statistical non-inferiority can be claimed. When including the
Film-forming Solution and Other Topical Treatments Klaschka study, the indirect comparison between terbinafine 1% FFS
The results of the meta-analyses in which terbinafine 1% FFS was and naftifine 1% gel or cream results in an effect of 1.9±10.0% to the
indirectly compared with the other active treatments are summarised advantage of terbinafine 1% FFS. This difference is not statistically
in Table 2 and Figure 2. significant (p=0.850) or clinically relevant (less than 10%). Here, too, the
lack of precision is due mainly to the heterogeneity of treatment effect
Terbinafine sizes among studies, explained itself by the Klaschka study. The lower
The indirect comparison between terbinafine 1% FFS and terbinafine bound of the 95% CI (-17.7%) is less than -10%, and statistical non-
1% cream results in an effect of -0.8±9.2% to the advantage of inferiority cannot be claimed anymore.
terbinafine 1% cream. This effect is not statistically significant
(p=0.931) or clinically relevant (<10%). Therefore, from a descriptive The Azoles
perspective, terbinafine 1% FFS can be considered to be non-inferior Bifonazole
to terbinafine 1% cream. The lack of precision, partially explained by The indirect comparison between terbinafine 1% FFS and bifonazole
the low number of trials and the heterogeneity of treatment effect 1% results in an effect of 9.6±11.0% to the advantage of terbinafine 1%
sizes among studies, is reflected in the length of the CI of the overall FFS. Although this effect is almost minimally clinically relevant (i.e.
treatment effect. Therefore, the lower bound of the 95% CI (-18.9%) is close to 10%), it is not statistically significant (p=0.384). From a
less than -10%, and statistical non-inferiority cannot be claimed. The descriptive perspective, terbinafine 1% FFS can be considered to be
indirect comparison between a single terbinafine 1% FFS and non-inferior to bifonazole 1% in this analysis. However, the lower
terbinafine 1% cream, solution or gel results in an effect of bound of the 95% CI (-12.0%) is less than -10%, and thus statistical
-4.4±7.0% to the advantage of terbinafine 1% cream, solution or gel. non-inferiority of terbinafine 1% FFS to bifonazole 1% cannot be
This effect is not statistically significant (p=0.532) or clinically relevant claimed. Of note, the length of the 95% CI can be explained by the
(<10%). From a descriptive perspective, a single application of heterogeneity of treatment effect sizes among studies and particularly
terbinafine 1% FFS can be considered as non-inferior to terbinafine by the Smith study.
EUROPEAN DERMATOLOGY 23
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