Previous clinical trials on hyaluronic acid (HA) fillers mainly reported results of treatment on a single area of the face, especially nasolabial folds (NLF).1,21,2 However, nowadays focus has shifted from individual indications to treating multiple areas at the same time to produce a better overall aesthetic outcome.3–73–73–73–73–7
A unique feature of Emervel HA dermal fillers (HAEL; Galderma SA, Lausanne, Switzerland) is that each variant has a different degree of cross-linking and particle calibration (Optimal Balance Technology) to provide optimal gel texture and enhanced integration into a different skin layer or area.5,65,6 The moderately firm texture and large gel calibration of HAEL Volume has been specifically designed to provide volumizing effect in cheekbones, cheeks, chin, or the facial oval.8 The gel firmness allows HAEL Volume to resist strong deformation, resulting in long-lasting volume enhancement.9 As one of the main barriers to cosmetic treatments is pain, HAEL Volume contains 0.3% lidocaine.
HAEL Volume Lidocaine received CE mark approval in Europe in 2009 for injection into the supraperiostic zone or subcutaneous fat tissue for the correction of facial volume (cheeks, chin) and has been approved in several other countries, including Brazil. The present study aimed to extend the indications of HAEL Volume to treat other facial areas.
The objective of this study was to assess the long-term performance of HAEL Volume for full-facial volume restoration by simultaneously treating between 2 and 6 indications among chin, temporal areas, jawline, cheek, cheekbones, and NLF. Tolerability and subject satisfaction were also evaluated.
Study Design and Subject Selection
This open, multicenter study included 60 subjects at 4 centers in Brazil over 18 months. The study was reviewed and approved by an Independent Ethics Committee and conducted in compliance with the Declaration of Helsinki, Good Clinical Practices, and local regulatory requirements. All subjects provided signed informed consent.
Male or female subjects were required to be aged ≥18 years, with a score of at least 2 (visible depression or descent) on the 4-point volume loss scale (VLS) for the full face, and at least 2 indications affected among chin, temporal areas, jawline, cheek, cheekbones, and NLF. For NLF, a severity score of at least 4 (deep wrinkle, well-defined edges) on the 6-point Lemperle rating scale (LRS) was required and cheekbones had to be injected concomitantly.
Main exclusion criteria included active skin disease, irritation, or inflammation of the face; previous injection of any permanent facial filler; facial laser treatment/chemical peel within 3 months; injections of botulinum toxin A or nonpermanent dermal fillers within 6 months; and aesthetic facial surgery within 12 months.
HAEL Volume, consisting of 20 mg/mL of HA and 3 mg/mL of lidocaine, was supplied in a single-use sterile 2.0 mL syringe with a 23 G ultrathin wall needle. Injections were performed in 2 to 6 indications at baseline with optional touch-up injections 3 weeks later. The choice of the injection technique, injection depth (into the supraperiostic zone or subcutis), and injected volume was at the discretion of the investigator.
Evaluation and Statistical Methods
Efficacy performance assessments of VLS, LRS, and investigator Global Aesthetic Improvement Scale (GAIS) were performed (for each treated indication and for the full face) at baseline, 3, 6 weeks (if touch-up injections), and then 3, 6, 12, and 18 months after last injection. The VLS ranged from 0 to 3, the LRS for NLF ranged from 0 to 5, and the GAIS was evaluated using a 5-point scale from −1 (worse) to 3 (very much improved).10–1210–1210–12
Subjects at 2 sites underwent Vectra (Canfield Scientific Inc., Fairfield, NJ) 3-dimensional (3D) digital imaging at all study visits. Vectra application software automatically generated the 3D-active photogrammetry model and differences in 3D surfaces were measured using volume assessment algorithms to calculate anatomical volume variations from baseline for each treated area.
Subject satisfaction questionnaires were completed 3 weeks and 18 months after last injection. Investigator questionnaires were completed after the last visit of the last subject.
Local tolerance that was severe or requiring treatment was recorded as an adverse event (AE). Local tolerance, AEs, and pain were recorded by investigators (at each study visit) and by subjects (in a daily diary for 21 days postbaseline).
All variables were summarized for the intent-to-treat population with descriptive statistics by evaluation time point. For evaluation of local tolerance, when both right and left areas were injected, the worst score was analyzed for each indication at each visit. For the anatomical volume measurements, the mean across both areas was analyzed.
Between February 2012 and March 2013, 60 subjects were included; all completed the study. Subjects had a mean age of 53.5 years (Table 1). At baseline (before injection), all 60 subjects had a full-face VLS score of 2 to 3 and all 56 subjects undergoing NLF injections had a baseline LRS score of 4 or 5.
Most subjects (71.6%) had 3 or 4 indications injected with the most common being cheekbones (96.7%) and NLF (93.3%) (Table 2). Mean total injection volumes per subject ranged from 1.0 mL for temporal areas to 2.7 mL for NLF, with a mean volume of 7.4 mL (6.7 mL baseline and 2.1 mL touch-up) for the full face (Table 2).
Retrograde linear threading was the most commonly used injection technique (50.0%–78.9% depending on the indication) and the provided needles (size 23 G) were used in all cases, except for temporal area injections in 2 subjects using 25 G needles.
At 3 weeks after the last injection, all subjects (100%) showed at least a 1-grade improvement in full-face VLS and this was sustained at other time points (68.3% still improved at 18 months) (Figure 1A). For individual indications, at least a 1-grade improvement in VLS was observed at 18 months for chin (77.8%), temporal areas (73.7%), cheeks (66.6%), cheekbones (58.6%), and jawline (43.2%) (Figure 1B, C). At 3 weeks after the last injection, the LRS for NLF was improved in almost all subjects (98.2%) and most subjects (71.4%) still showed improvement at 18 months (Figure 2).
According to 3D digital imaging, an increase in mean 3D volume was observed for all indications at 3 weeks after the last injection (optimal correction). When the volume at 18 months was compared with the optimal correction, more than 60% of the volume gained was sustained for all indications (Figure 3).
A representative 3D image analysis volume model and 3D photographs for the same subject are shown in Figures 4 and 5. Additional 3D photographs are shown in Figure 6.
Investigators judged full-face GAIS to be improved for all subjects at 3 weeks after last injection, which persisted after 18 months (95.0%) (Figure 7A). Similar GAIS results were obtained for the individual indications, for example, cheekbones and cheeks (Figure 7B, C).
All subjects were satisfied with their aesthetic outcome and considered that the results met or exceeded their expectations (Figure 8). At 18 months after the last injection, 78.3% of subjects reported that the treatment had given them more self-esteem and confidence. Most subjects (94.9%) reported being satisfied (25.9%) or very satisfied (69.0%) with the comfort of the injections. All subjects indicated they would recommend the treatment to family/friends and would like to receive the treatment again. At 18 months after the last injection, 98.3% of subjects were satisfied or very satisfied with the durability of the results.
Furthermore, all investigators who injected subjects (7 injectors) responded that they would use HAEL Volume again.
Most subjects had injection site reactions immediately postinjection. The most common investigator-assessed events were edema in 50.0% to 68.6% subjects depending on the indication; they were predominantly mild in intensity (in 22.2% to 44.6% of subjects) and had disappeared by the follow-up visit 3 weeks later. Similarly, erythema was reported in 36.8% to 62.5% of subjects depending on the indication (mild in 37.0% to 51.7% subjects). Investigators reported few cases of postinjection bruising (0%–16.1% of subjects depending on the indication). Investigator-assessed nodule formation varied from 1 subject (in chin, temporal areas, cheeks) to 5 subjects (9.8%) in jawline; most cases were mild.
Subject-assessed tolerance during the 3-week postinjection period reported swelling (edema) and bruising as the most common signs across all indications (Table 3); they were mild in severity and almost all had disappeared by the next visit. Subjects reported almost no pain at all (Table 3).
Only 1 subject (1.6%) had treatment-related AEs, which were moderate in intensity, limited to the injection site (6 bruises), and resolved without treatment before the next visit 3 weeks later. There were no severe AE or AEs leading to study discontinuation.
In this open multicenter study, most subjects (71.6%) received injections for 3 or 4 indications, indicating a study population in need of full-facial aesthetic filler treatment. The full-facial approach is important from an anatomical perspective as treatment of some indications can lead to changes in other areas of close proximity.5
At 18 months after the last injections, more than two-thirds of subjects showed an improvement from baseline in full-face VLS and similar results were obtained for all individual indications, especially chin, temporal areas, cheeks, and cheekbones. Furthermore, 55.0% of subjects were still much improved at 18 months for GAIS aesthetic improvement of full face, with similar results for individual indications, especially cheekbones (58.6%).
Since VLS and GAIS scores are subjective scores, the authors also used the more objective quantitative method of 3D analysis to corroborate the results.13 It is noteworthy that with 3D imaging there is always a potential for variation due to changes in facial expression, for example, minor differences in the jaw and mouth position can affect the volumetric differences in the cheeks and jawlines, as well as the chin. Regardless, 3D imaging consistently demonstrated across all indications that more than 60% of the 3D volumetric measurement results of the optimal effect gained at 3 weeks were sustained at 18 months.
This 18-month study supports and extends earlier findings obtained regarding the good efficacy and tolerability of HAEL Volume in cheek enhancement over 6 months.8 The correction achieved at 3 weeks (optimal correction) was well maintained at 6 months with 65.8% volume maintained in terms of cheek thickness caliper assessments and 67.7% in terms of 3D volume analysis.8 In another 6-month open-label study (40 subjects), mid-face volume loss was corrected using large gel particle HA with lidocaine (Restylane Perlane-L; Galderma) and 92.5% of subjects had at least a 1-grade improvement in the Medicis Midface Volume Scale at 6 months.14
Persistent improvements have been reported up to 12 months post-treatment with nonanimal stabilized HA (Restylane SubQ; Galderma) for augmentation of the cheeks and chin.15 In an open-label study (n = 57), aesthetic improvement in chin or cheek or both was maintained in 52% of subjects at 12 months.3
Although not full-face rejuvenation, 2 previous studies on HA filler (Juvederm Voluma; Allergan Inc., Irvine, CA) use in the malar area were longer than 18 months.4,164,16 In an open study, 43.7% of subjects did not require supplementary treatment at 18 months postbaseline; however, the patients were younger than in the present study (47 years on average).4 Also, in a randomized study (n = 235), nearly half the subjects maintained correction for 24 months.16
To the knowledge of the authors, the present 18-month study is the only long-term study demonstrating enduring full-facial rejuvenation. Furthermore, the present study also demonstrated no decline in subject satisfaction over the 18-month study period and all subjects were satisfied with the durability of the results reflecting the long-lasting effectiveness of HAEL Volume.
One consequence of using a full-face approach is the rather large quantity of filler injected per subject. Each treatment was customized to suit each individual's skin quality, tissue cover, skin laxity, and severity of volume loss while satisfying the subject's aesthetic expectations. In these subjects with a mean age of 53.5 years and showing advanced signs of aging, the mean total volume injected (baseline and touch-up combined) was 7.4 mL. However, this total volume was spread over several indications (3.7 indications on average) and so was consistent with the quantities used in other clinical studies.3–5,8,14,163–5,8,14,163–5,8,14,163–5,8,14,163–5,8,14,163–5,8,14,16
Despite the large volumes of HAEL Volume used, the product was well tolerated. Apart from the mild-to-moderate local injection site reactions, only 1 subject experienced any related AEs (bruising) and all were transient and resolved without sequelae. Furthermore, the injection procedure for this formulation of HAEL Volume containing lidocaine was almost painless, which no doubt contributed to the high patient satisfaction.
A limitation of this study is its open design, which did, however, have the advantage of allowing investigators to choose the indications, the volume, and injection technique while taking into consideration the patient's desires and expectations and thus provide personalized treatments.
In conclusion, volume restoration of the aging face with HAEL Volume was sustained over 18 months for the full face as for all indications, particularly in the mid-face area, as demonstrated by subjective volume restoration assessments and objective 3D imaging assessments. The long-lasting performance and good safety profile gave high patient satisfaction and support the use of HAEL Volume filler for full-facial rejuvenation.
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