15018752330
发表时间:2015-12-08 浏览次数:535次
Introduction
Neurotoxin injection accounted for more than a third of all nonsurgical
cosmetic procedures performed in the United States in 2012. [1]
Abobotulinumtoxin A (aboBTX-A, dysport) and onabotulinumtoxin A
(onaBTX-A, Botox) are currently the most commonly used preparations of
Clostridium botulinum toxin in the treatment of glabellar frown lines.
Composed of high-molecular weight protein complexes unique to the
various formulations, each of these neuromodulators has a slightly
different pharmacokinetic profile. [2]
The protein complex is also thought to play a role in the
immunogenicity of these therapeutic agents, influencing tolerance to
drug effect and clinical response over time. [3]
Abobotulinumtoxin A (aboBTX-A, dysport) is a type A botulinum toxin
approved for the temporary improvement in the appearance of moderate to
severe glabellar lines associated with procerus and corrugator muscle
activity. [4]
The toxin exists in a protein complex approximately 500 kDa in size.
Incobotulinumtoxin A (incoBTX-A, xeomin), a recently approved form of
botulinum toxin type A, is also indicated for the temporary improvement
in the appearance of moderate to severe glabellar lines associated with
corrugator and/or procerus muscle activity in adult patients. [5]
IncoBTX-A differs from the other neuromodulators, including onaBTX-A
and aboBTX-A, in its formulation as a purified toxin-free of complexing
proteins. This formulation, in theory, renders incoBTX-A less
immunogenic than the other forms of botulinum toxin A currently
available, permitting reproducible effects on repeat injections.
Although
a calculated unit conversion between alternative neurotoxin
preparations cannot be directly derived due to differing manufacturing
processes, the separate bacterial strains involved, and the variations
in size of the associated complexing proteins, [2],[6],[7]
a published clinical study as well as the senior author's clinical
experience has shown that a reliable conversion rate between aboBTX-A
(dysport) and onaBTX-A (Botox) is 2.5:1. [8] In addition, several studies have concluded that a 1:1 equivalency exists between onaBTX-A (Botox) and incoBTX-A (xeomin). [9],[10]
In our practice since 2010, the majority of patients treated with
neuromodulators receive aboBTX-A. Given the potentially promising
immunogenic profile of incoBTX-A, [11]
we were interested in determining the correct dosage of this
neuromodulator among our patient population. Due to the uncertainty
regarding conjectural conversion between the three neurotoxin
preparations, we sought to establish effectiveness and dosing
equivalency of incoBTX-A versus aboBTX-A within a consecutive series of
32 patients previously treated with aboBTX-A for temporary reduction in
glabellar dynamic wrinkles.
Methods
We conducted a prospective pilot study at a single surgeon center, with
all injections performed by the senior author. The study included
patients that had previously received at least four consecutive
treatments of aboBTX-A at 4-month intervals at a stable dose, achieving
85-90% elimination of dynamic glabellar frown lines, and who had
expressed satisfaction with at least four consecutive aboBTX-A
treatments. Patient satisfaction with aboBTX-A treatment was defined by
the patient's decision not to return for re-treatments before the
planned redosing interval of 4-month.
Primary outcomes of this
pilot study were patient perceived clinical effectiveness at 2 weeks
(defined as an 85-90% decrease in muscle activity) and percentage of
muscle activity at 3 months per surgeon assessment. The planned
conversion rate was 2:1 (aboBTX-A: incoBTX-A) using the established
aboBTX-A dosage for each patient to determine an initial incoBTX-A dose.
However, we permitted dose adjustment per the physician's assessment at
the time of incoBTX-A injection. The incoBTX-A dose was dispersed into
the corrugator and procerus muscles for each patient; injection patterns
were based on diagrams reviewed in the electronic medical record,
documenting the injection points used during prior aboBTX-A treatments.
Secondary
outcomes were examined via patient questionnaires that asked subjects
to report on the onset of effect after incoBTX-A injection, the pain of
injection versus their recollection of pain on aboBTX-A injections, the
perceived duration of effect, and their overall satisfaction with the
treatment session. Patients who were not satisfied with their initial
treatment dosage were asked to return for re-treatment at 2 weeks. All
patients were seen in follow-up at 10-12 weeks. At this time, glabellar
and procerus activity were assessed by the treating surgeon, and the
patient's perception of the treatment was recorded.
Demographic
and clinical characteristics were summarized using frequency counts and
percentages for categorical variables and median and range for
continuous variables. Residual muscle activity at 4-month following at
least four abobotulinumtoxin A treatment sessions was compared to muscle
activity with one incobotulinumtoxin A treatment session at 10-12 weeks
using a paired t-test.
Results
A total of 32 subjects were included. The majority of patients were female (40-71 years old) and most had received aboBTX-A consistently for over 2 years [Table 1]. The mean dose of incoBTX-A administered was 17.1 units (± 6.1, median dose 20 units). The mean treatment dose of aboBTX-A administered was 27.6 (± 11.7, median dose 27.5 units). The mean difference in treatment units was -10.5 (95% confidence interval, P < 0.001) [Table 2]. Among 30 patients who reported effect onset of the one incoBTX-A treatment, the median result was 8.5 days, with a range of 1-14 days [Table 1].
Twenty-nine out of 32 patients (91%) reported satisfactory treatment
effect at 2 weeks, 3 patients (9%) requested re-treatment at 2 weeks
with aboBTX-A due to perceived lack of effective treatment with
incoBTX-A. During follow-up with the treating surgeon at 10-12 weeks,
muscle paralysis was assessed to be 69.2% (± 27.3), vs. 90.3% (± 1.8) in an equivalent time period with aboBTX-A (P < 0.001) [Table 2].
With regard to perceived pain on injection, 62% of patients reported
equivalent pain between the two treatments, 22% of patients reported
more pain with the incoBTX-A injection, 9% had less pain with incoBTX-A,
and 6% were unable to reliably recall. Overall satisfaction with
incoBTX-A treatment was confirmed by 22 out of 32 patients among the
study group (68%) at 2 weeks; this increased to 25/32 (78%) at 3 months.
The most commonly cited reasons for dissatisfaction were related to the
longevity and magnitude of incoBTX-A's effect.
At 10-12 weeks
following incoBTX-A treatment, the percentage of muscle activity was
recorded by the senior surgeon in light of the dose ratio of aboBTX-A:
incoBTX-A administered. Of the subjects that received an incoBTX-A dose
at a ratio of 1.5-2.5:1, only 40% had a clinical result that was
considered equivalent to the original four aboBTX-A treatment dose
results. A total of 16% of patients had effects that were less than
expected for the hypothesized ratio. Some patients (38%) received
relatively more incoBTX-A (ratio of 0.5-1.5:1), due to clinical
evaluation that the dose should be higher than 2:1 of the original
aboBTX-A dose. Among this study group, 16% resulted in muscle
attenuation that was greater than perceived with the aboBTX-A dose,
whereas 22% had a less than expected response. Six percent of patients
had a lesser response while receiving a relatively lower dose (ratio of
2.5-3:1) [Figure 1].
Discussion
Injection of botulinum toxin type A was the most commonly performed
cosmetic procedure in the Unites States in 2012, with over 4 million
treatments reported for the year. [1]
Together with other injectable products, treatment with botulinum toxin
type A accounted for approximately 2 billion dollars of Unites States
spending in 2012. The rising number of minimally-invasive cosmetic
procedures being performed, with a 10% increase in such procedures noted
from 2011 to 2012, signals the long-term impact that injection of
botulinum toxin type A and other nonsurgical procedures will have on the
future of aesthetic practices.
Reported overall patient satisfaction rates with botulinum toxin type A treatments are high [7],[12] and are largely related to the onset, duration, and efficacy of treatment. [7]
Given the tremendous impact of neuromodulator therapy and the
importance of patient satisfaction as a key outcome, it is essential for
practitioners to understand the optimal treatment dose, re-treatment
interval, and expected outcomes associated with the various botulinum
toxin A preparations available today.
Multiple clinical studies
have demonstrated the safety, efficacy and tolerability of aboBTX-A
since its Food and Drug Administration (FDA) approval in 2009 for the
treatment of glabellar frown lines. [13],[14],[15],[16]
A prospective, randomized control split-face trial comparing aboBTX-A
with onaBTX-A found no significant differences between treatment effects
on muscle activity or wrinkle appearance, onset and duration of
treatment effect, or diffusion characteristics of the two neurotoxins. [8]
Although one clinical trial is comparing onaBTX-A with aboBTX-A
indicated lower rates of patient satisfaction among patients treated
with aboBTX-A, [17]
satisfaction rates with aboBTX-A treatments were high among our patient
population. All our patients had previously received at least four
consecutive treatments of aboBTX-A at 4-month intervals at a stable dose
and had continued to achieve 85-90% elimination of dynamic glabellar
frown lines at this dose with a reported high patient satisfaction rate.
Free
of complexing proteins, incoBTX-A is unique among the botulinum toxin
preparations currently available. The subtraction of these inactive or
denatured protein complexes theoretically results in a lower antigen
load, decreasing the chance that the subject will develop neutralizing
antibodies to treatment over time that could result in diminished
clinical efficacy. [11],[18]
IncoBTX-A received FDA approval for the treatment of glabellar frown
lines in 2011, and a phase III clinical trial conducted that same year
confirmed its efficacy for this indication, in accordance with
FDA-mandated scoring criteria. [19]
One comparative trial of onaBTX-A and incoBTX-A reported overall high
rates of patient satisfaction with both treatments and no statistically
significant difference in satisfaction rates between the two
neuromodulators. [20]
A noninferiority trial comparing incoBTX-A with onaBTX-A found similar
efficacy, safety, and patient satisfaction profiles between the two
treatments at a 1:1 dosing ratio. [10] No head-to-head trials comparing incoBTX-A with aboBTX-A have been published to date.
As such, our pilot study aimed to determine a dosing equivalency of incoBTX-A vs.
aboBTX-A that would result in similar clinical effectiveness and
patient satisfaction among 32 patients previously treated with aboBTX-A
for at least four treatments over 1 year. At ratios believed to
anticipate equivalent results based on prior dose comparison studies, [8],[9],[10] we found that no precise ratio could be determined.
Among
the patients who reported effect onset with incoBTX-A treatment, the
median result was 8.5 days, longer than the median onset of effect with
aboBTX-A treatment reported in the literature of 3 days. [21],[22]
Limitations of our study include its small sample size, larger studies
are warranted to better establish dose equivalency between aboBTX-A and
incoBTX-A. IncoBTX-A injections were performed without cost to the
patient, and this may have affected patient satisfaction rates.
Secondary outcomes were determined through the use of a patient
questionnaire. Recall bias may have affected our patients' ability to
compare the pain of incoBTX-A injection compared with aboBTX-A injection
which had occurred several months prior, and patient-reported onset and
duration of effect may not be the most accurate means available of
recording these results. However, given the elective nature of treatment
to improve patient cosmesis, we believe that the patient report, while
inherently biased, is still an acceptable method of outcome assessment.
In conclusion, the pilot study did not establish a dose equivalency between incobotulinumtoxin A (xeomin) vs.
abobotulinumtoxin A (dysport) in the treatment of dynamic glabellar
frown lines in 32 consecutive patients who previously reported treatment
success with abobotulinumtoxin A for at least 1 year at 4-month
intervals. By combining the analysis of both the patient-reported
results and the objective evaluation of dynamic glabellar muscle
activity at 10-12 weeks following one treatment session with incoBTX-A,
we found that using incoBTX-A at 17.1 (± 6.1) units was less predictable
than using aboBTX-A at 27.6 (± 11.7) units. In comparison to aboBTX-A,
the majority of our patients also reported lower satisfaction rates with
incoBTX-A treatment; this difference was attributed to longer onset to
treatment effect, increased pain on injection, and shortened duration of
effect. Larger, prospective, randomized controlled studies are
warranted to better establish dose equivalency between abobotulinumtoxin
A and incobotulinumtoxin A.
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