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10760512
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Publication:
Dermatologic Surgery
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34 (2) p.210-215
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2/2008
Calcium Hydroxylapatite versus Nonanimal Stabilized Hyaluronic Acid for the Correction of Nasolabial Folds: A
12-Month, Multicenter, Prospective, Randomized, Controlled, Split-Face Trial
Author(s):
MOERS-CARPI, MARION MICHAELA; TUFET, JAIME OPI
Date
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Calcium Hydroxylapatite versus Nonanimal Stabilized
Hyaluronic Acid for the Correction of Nasolabial Folds:
A 12-Month, Multicenter, Prospective, Randomized, Controlled,
Split-Face Trial
MARION MICHAELA MOERS-CARPI, MD,
AND
JAIME OPI TUFET, MDy
BACKGROUND Fillers continue to proliferate in dermatology. Rigorous clinical trials can help determine the advantages and disadvantages of these products as they come to market.
OBJECTIVE This randomized, split-face, controlled study compared the efficacy, safety, durability, and
volumes of calcium hydroxylapatite (CaHA) versus nonanimal-stabilized hyaluronic acid (NASHA) in
nasolabial folds.
METHODS AND MATERIALS Sixty patients were enrolled at two medical clinics in Europe (Summer
2005). Patients received two injections 3 months apart. Patients returned at 6, 9, and 12 months for a
blinded evaluation, using accepted aesthetic rating scales. Adverse events were recorded throughout
the study.
RESULTS At all time points, CaHA was found to be more effective than NASHA. At 12 months, 79% of
CaHA folds were still improved or better versus 43% of NASHA folds (po.0001). In addition, 30% less
total CaHA volume was required compared to NASHA. Evaluators assessed CaHA as superior in 47% of
patients and inferior in only 5% (po.0001). Blinded evaluators and patients preferred CaHA two to one (p
o.05). Both products were safe and well tolerated.
CONCLUSION CaHA was found to be significantly more effective than NASHA. At all time points, CaHA
demonstrated longer lasting results and greater improvement than NASHA.
Bioform Medical, Inc. (San Mateo, CA), provided Radiesse, study funding, and photographic documentation
equipment to the authors. Dr. Moers-Carpi also received compensation for presentations about Radiesse to
the medical community.
N
oninvasive treatments as supplementaryFand
complementaryFoptions to surgery have increasingly become an acceptable part of the aesthetic
caregiver’s regimen. In the United States, for example, from 1997 to 2005, the number of nonsurgical
procedures rose from approximately 1 million to
more than 9 million; the number of surgical procedures rose from approximately 1 million to just over
2 million.1
Soft tissue fillers, along with neurotoxin-induced
denervation, constitute a large part of the nonsurgical category. In the past, collagen products (bovine,
autogenic, and isogenic) and hyaluronic acid deriv-
atives have often been the products of choice for soft
tissue fillers.2–5 Earlier studies have compared collagen to two distinct hyaluronic acid formulations.2,6
Both of those important studies used the same ratings systemsFthe Global Aesthetic Improvement
Scale (GAIS)2 and the Wrinkle Severity Rating Scale
(WSRS).7
Also using the WSRS and the GAIS, this article reports the results of a comparison study of calcium
hydroxylapatite (CaHA; Radiesse, Bioform Medical,
Inc., San Mateo, CA) to nonanimal-stabilized
hyaluronic acid (NASHA; Restylane, Medicis
Aesthestics Inc., Scottsdale, AZ) for the correction of
Private Clinic, Hautok, Munich, Germany; yPrivate Clinic, Barcelona, Spain
& 2007 by the American Society for Dermatologic Surgery, Inc. Published by Blackwell Publishing ISSN: 1076-0512 Dermatol Surg 2008;34:210–215 DOI: 10.1111/j.1524-4725.2007.34039.x
210
MOERS-CARPI AND TUFET
nasolabial folds. In late December 2006, Radiesse
received U.S. Food and Drug Administration approval for subdermal implantation for the correction
of moderate to severe facial wrinkles and folds, such
as nasolabial folds, and for restoration and/or correction of the signs of facial fat loss (lipoatrophy) in
people with human immunodeficiency virus.
Methods
Study Objective
The objective of this study was to assess the effectiveness and longevity of CaHA versus NASHA
for the correction of nasolabial folds.
Patient Population
Sixty patients were enrolled in the trial (52 females
and 8 males). The mean age was 50.5 years (range
34–67 years). Enrolled patients had moderate to
severe nasolabial folds, i.e., a rating of 3 or 4 on
the WSRS.
Design
The study was a multicenter (Germany and Spain),
prospective, randomized, split-face, controlled trial.
Ethics committee approval was obtained before
study initiation. Inclusion criteria were as follows:
right and left nasolabial fold with a rating of 3 or 4
on WSRS by the blinded evaluator, 18 years of age or
older, signed written informed consent, understood
and accepted the obligation not to receive any other
facial procedures through 12-month follow-up, understood possibility of unevenness in the nasolabial
folds that would not be corrected until the 12-month
follow up visit, and understood and accepted the
obligation and would be logistically able to appear
for all scheduled follow-up visits. The study protocol
conformed to the guidelines of the 1975 Declaration
of Helsinki.
Exclusion criteria were as follows: known bleeding
disorder; history of keloid formation or hypertrophic
scarring; chronic or recurrent infection or inflammation that would preclude participation in the
study; severe allergies manifested by history of anaphylaxis; being pregnant, lactating, or not using reliable contraceptive methods (if applicable); had
received or anticipated receiving antiplatelets, anticoagulants, thrombolytics, vitamin E, or anti-inflammatories from 1 week before to 1 month after
injection; was receiving systemic corticosteroids or
anabolic steroids; had received silicone injections,
grafting, any other surgery, or facial tissue augmentation other than CaHA, collagen, or hyaluronic acid
in either nasolabial fold within the 6 months before
enrollment; the presence of any condition contraindicated in the Restylane labeling; or use of over-thecounter wrinkle products (e.g., a-hydroxy acids) or
prescription treatments (e.g., Renova, Retin-A, microdermabrasion, chemical peels) within 4 weeks
before study or intent to receive these products
and/or treatments during the study.
After pretreatment photography using standard
technique, anesthetization of the nasolabial folds was
performed at the discretion of the treating physician
(the physician at the 50-patient German site used no
anesthetic; the physician at the 10-patient Spanish
site used topical or local anesthetizing agents) and the
same tracking (or threading) injection technique was
used on both folds. Both products were injected with
a 27-gauge needle into the mid to deep dermis. At the
initial visit, each patient was treated with CaHA to
correct one nasolabial fold and NASHA to correct
the other fold. Patients born in an even-numbered
year received CaHA in the right fold; patients born in
an odd-numbered year received CaHA in the left
fold. The volume of injection of CaHA and NASHA
necessary for full correction was at the discretion
of the treating physician. Physicians were advised to
inject enough material to create a robust augmentation and achieve good long-term results. In addition
to the above injection instructions, the products were
used according to the instructions for use for both
products, inclusive of all stated precautions and
warnings.
After the initial injection, all patients returned at 3, 6,
9, and 12 months for follow-up. At the 3-month visit,
3 4 : 2 : F E B R U A RY 2 0 0 8
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CaHA VERSUS NASHA FOR THE CORRECTION OF NASOLABIAL FOLDS
TABLE 1. GAIS Distribution: CaHA versus NASHA at 6, 9, and 12 Months
6 months (n = 59)
9 months (n = 58)
12 months (n = 58)
CaHA
NASHA
CaHA
NASHA
CaHA
NASHA
Very much improved (%)
Much improved (%)
Improved (%)
No change (%)
Worse (%)
61
22
14
3
0
32
27
31
10
0
14
22
52
10
2
0
17
38
38
7
3
9
67
21
0
2
2
40
48
9
Total improved (%)
p Value
97
90
88
55
79
.05
o.0001
44
o.0001
Using McNemar’s test.
patients received a touch-up treatment in both folds,
ensuring that correction was maintained. Before
touch-up, photographs of the patient’s lower face were
taken using the same photography procedure used for
enrollment photos. At the 6-, 9-, and 12-month visits,
all patients returned for a GAIS rating and a WSRS
rating by the blinded evaluator, product preference
rating by both the patients and the blinded evaluator,
and additional photographs of their lower face. Fiftyeight of the 60 patients completed the study through
12 months; 2 patients were lost to follow-up.
The GAIS rating was determined by comparing the
patient’s live appearance to the baseline photograph.
The WSRS rating was determined by evaluating the
patient’s live appearance. Safety was assessed by recording all local and systemic adverse events observed for all patients from injection through 12month follow-up. Information provided included
type, location, duration of the event, and a description of any treatment that may have been given.
terms of product preference, both evaluators and
patients preferred CaHA by a two-to-one margin
(po.05). In other words, both patients and evaluating
physicians had general agreement as to which product
they preferred. The results of the 6-, 9-, and 12-month
ratings are shown in Tables 1 through 3.
WSRS Ratings Not unlike the GAIS ratings, at
12 months, the WSRS evaluator ratings showed
that 31% of the CaHA-treated folds showed greater
improvement than the NASHA-treated folds; only
7% of NASHA-treated folds were rated as greater
(po.0001). In addition, in the CaHA-treated fold,
the mean change in WSRS at 9 months was 0.71,
whereas the NASHA-treated fold showed only 0.41
mean change. At 12 months, the CaHA mean change
was 0.43; the NASHA mean change was 0.14
(p = .007). Representative serial photographic images
of nasolabial folds treated with CaHA and with
NASHA are shown in Figures 1 and 2.
Injected Volumes The mean volume required for
correction in the fold treated with CaHA was 30%
Results
Effectiveness
GAIS Ratings In summary, at 12 months, GAIS ratings showed 79% of CaHA-treated folds as very much
improved, much improved, or improved, compared
to 43% of the NASHA-treated folds (po.0001).
Blinded evaluators determined that nearly 47% of the
CaHA-treated folds were superior to the NASHAtreated folds; only 5% were inferior (po.0001). In
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D E R M AT O L O G I C S U R G E RY
TABLE 2. GAIS Superiority: CaHA Compared to
NASHA at 6, 9, and 12 Months
Superior (%)
Same (%)
Inferior (%)
6 months
(n = 59)
9 months
(n = 58)
12 months
(n = 58)
37.3
55.9
6.8
56.9
36.2
6.9
46.6
48.3
5.2
All p values o.0001 using binomial distribution.
MOERS-CARPI AND TUFET
TABLE 3. Blinded Evaluator and Patient Preference: CaHA versus NASHA at 6, 9, and 12 Months
6 months (n = 59)
CaHA (%)
NASHA (%)
9 months (n = 58)
12 months (n = 58)
Blinded evaluator
Patient
Blinded evaluator
Patient
Blinded evaluator
Patient
66
34
64
36
69
31
64
36
69
31
67
33
All p values o.05 using binomial distribution.
less than the volume of NASHA required for the
opposite fold (0.88 mL of CaHA vs. 1.26 mL of
NASHA).
Safety
Both products were safe and well tolerated, with no
serious adverse events reported for either CaHA or
NASHA treatment. Four adverse events were
reported in this study. These included two
hematomas, one nodule, and one extrusion, of
118 folds injected two times each during the
course of the study. The hematomas and the
nodule appeared on the CaHA-treated fold.
The two hematomas resolved in 4 to 5 days,
with no further complications; the nodule was
treated with 0.2 mL of triamcinolone acetonide
and was cleared in 14 days. The extrusion
appeared in the NASHA-treated fold; it was
treated with antibiotics and resolved
without complications.
Statistical Methods
Statistical comparisons were made with regard to
GAIS, WSRS, and product preference. For the GAIS
Figure 1. A 56-year-old female, who received a total of 1.2 mL of NASHA in the right fold and a total of 0.8 mL of CaHA in the
left fold. Photos are baseline and then 6, 9, and 12 months after initial treatment (no photo after first treatment). GAIS ratings
at 6, 9, and 12 months were improved/very much improved, no change/much improved, and no change/improved, respectively. WSRS ratings at baseline and 6, 9, and 12 months were 4/3, 3/2, 4/2, and 4/3, respectively.
3 4 : 2 : F E B R U A RY 2 0 0 8
213
CaHA VERSUS NASHA FOR THE CORRECTION OF NASOLABIAL FOLDS
Figure 2. A 54-year-old female, who received a total of 1.4 mL of NASHA in the left fold and a total of 0.8 mL of CaHA in the
right fold. Photos are baseline and then 6, 9, and 12 months after initial treatment (no photo after first treatment). GAIS
ratings at 6, 9, and 12 months were very much improved/very much improved, very much improved/much improved,
and much improved/no change, respectively. WSRS ratings at baseline, 6, 9, and 12 months were 4/4, 2/2, 1/2, and 2/4,
respectively.
superiority and product preference analyses, the binomial distribution was used and null hypothesis
was tested that the response rate was 50%. Patients
for whom there was no difference between the
products were excluded from the superiority analysis. For the GAIS distribution and the WSRS analyses, McNemar’s test and the Satterthwaite t test
were used, respectively. Statistical significance was
declared if the two-sided p value was r.05.
Discussion
In this statistically significant study, CaHA-treated
folds showed greater improvement than NASHAtreated folds. Researchers found that 79% of nasolabial folds treated with CaHA were still improved at
12 months, compared with 43% of nasolabial folds
treated with NASHA. GAIS ratings statistically significantly favored CaHA at all time points. The
214
D E R M AT O L O G I C S U R G E RY
mean change in baseline WSRS scores was statistically significantly in favor of CaHA at all time
points. Moreover, both evaluators and patients preferred CaHA to NASHA by a two-to-one margin.
Both products exhibited favorable safety profiles. As
an aside, the presence of lip nodules in patients
treated with CaHA has been noted,7 including one
patient in this study, who was diagnosed with
CaHA-related lip nodules after study completion.
Approximately one-third lower volume of CaHA
was required compared to NASHA to achieve the
desired aesthetic effect. Since CaHA and NASHA
cost approximately the same amount per milliliter,
this lower volume would result in lower cost per
treated fold for CaHA than for NASHA. This same
percentage was noted in the cost difference between
the two soft tissue fillers; the cost of CaHA was approximately 30% less than NASHA, based on list
MOERS-CARPI AND TUFET
price of $227/mL for CaHA and $245/mL for
NASHA. The list price for the CaHA 1.3-mL syringe
is $295; the product is not available in a 1.0 mL
syringe.
We look forward to reading of other physicians’
experiences with this new soft tissue filler.
References
The Narins comparison of this NASHA product
(Restylane) with bovine dermal collagen (Zyplast)2
described the results 6 months postbaseline; this
study describes the results of CaHA with NASHA
9 months after the second injection, i.e., 12 months
after baseline. In its duration of measurement, the
study uses the time frame that Lindqvist and colleagues5 used to compare another NASHA product
(Perlane) to bovine dermal collagen. In both the
Narins and the Lindqvist studies, researchers found
favorable results with the NASHA products compared with the collagen products. This study, in
contrast, advances the discussion with its comparison of a NASHA product and CaHA.
In this head-to-head study with NASHA, CaHA is the
first product to demonstrate greater durability and
comparable safety. We believe that CaHA will play a
significant role in the practice of many aesthetic
medicine practitioners. As aesthetic care providers
continue to embrace noninvasive strategies for facial
rejuvenation, we will continue to explore which tissue
fillers are most appropriate for which particular areas.
1. The American Society of Aesthetic Plastic Surgery. Cosmetic surgery national data bank; 2005 statistics [accessed July 2006]
Available from: http://www.surgery.org/download/2005stats.pdf
2. Narins RD, Brandt F, Leyden J, et al. A randomized, double-blind,
multicenter comparison of the efficacy and tolerability of Restylane
versus Zyplast for the correction of nasolabial folds. Dermatol Surg
2003;29:588–95.
3. Knapp TR, Kaplan EN, Daniels JR. Injectable collagen for
soft tissue augmentation. Plast Reconstr Surg 1997;60:
389–405.
4. Werschler WP. Radiesse and other soft tissue fillers: right
products, right place, right time. Aesthet Trends Technol
2006; 5(4): http://www.aesthetictrends.com
5. Lindqvist C, Tveten S, Bondevik BE, et al. A randomized, evaluator-blind, multicenter comparison of the efficacy and tolerability
of Perlane versus Zyplast in the correction of nasolabial folds. Plast
Reconstr Surg 2005;115:282–9.
6. Day DJ, Littler CM, Swift RW, et al. The Wrinkle Severity
Rating Scale: a validation study. Am J Clin Dermatol 2004;5:
49–52.
7. Jansen DA, Graivier MH. Evaluation of a calcium hydroxylapatitebased implant (Radiesse) for facial soft tissue augmentation. Plast
Reconstr Surg 2006;118(Suppl):22S–30S.
Address correspondence and reprint requests to: Marion
M. Moers-Carpi, MD, Residenzstrasse 7, Munich 80333,
Germany, or e-mail: DrMarion@hautok.de
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