1. This research was supported by Medicis Aesthetics Inc., Scottsdale, AZ, USA.
Introduction
77 Hyaluronic acid (HA) is an injectable dermal filler that is used in approximately 85% of soft-tissue
augmentation procedures in the United States.
77 Small gel particle HA (SGP-HA; Restylane®
) was the first HA gel approved by the U.S. Food and
Drug Administration (FDA), in 2003.
▪▪ Since that time, the development of new aesthetic techniques using HA fillers in clinical
practice has expanded far beyond the labeled indications.
77 SGP-HA and large gel particle HA (LGP-HA; Perlane®
) were chosen as the subjects of a systematic
investigation.
▪▪ SGP-HA is the most extensively described HA filler in the medical literature.
▪▪ SGP-HA and LGP-HA consist of well-defined gel particles that differ only in their particle sizes.
▪▪ Both products are “stiff” yet elastic compared with other HA fillers, permitting manipulation
immediately after injection while providing lift, volume, structural support, and definition to the
injected area.1-3
Objective
77 To prepare a systematic review of published primary clinical evidence on small
and large gel particle hyaluronic acid injectable fillers formulated with or
without lidocaine
Methods
Literature Search
77 PubMed was searched on June 21, 2011, for clinical studies and case reports that described
evidence for aesthetic uses of HA.
▪▪ No date or language limits were imposed.
77 Abstracts were manually reviewed to limit results to articles that reported results of aesthetic
treatment with SGP-HA, LGP-HA, or their lidocaine formulations (SGP-HA-L and LGP-HA-L).
77 Additional references were identified from the articles already retrieved, the bibliography of a
recent proceedings report,4
and the authors’ own libraries.
Analysis
77 All selected articles were analyzed in detail.
77 Data on anatomic treatment area, patient population, trial design, endpoints, effectiveness, and
safety were extracted from the full-text articles.
77 Level of evidence (LOE) was assigned according to criteria promulgated by the Oxford Centre for
Evidence-Based Medicine (Table 1).5
Table 1. Oxford Centre for Evidence-Based Medicine Levels of Evidence5
LOE* Criteria
1b Individual RCT (with narrow CI)
2b Individual cohort study (including low-quality RCT; e.g., <80% follow-up)
4 Case series (and poor-quality cohort and case-control studies)
LOE=level of evidence; RCT=randomized, controlled trial.
*Only LOEs assigned in this analysis are shown.
Results
Literature Search
77 The initial search identified 404 articles.
77 Applying analysis parameters yielded 53 articles for data extraction (Figure 1).
Endpoints
77 A wide variety of efficacy endpoints were used.
77 A minority of efficacy scales were validated, including the Wrinkle Severity Rating Scale (WSRS),
Modified Facial Wrinkle Scale (MFWS), Wrinkle Assessment Scale (WAS), Medicis Lip Fullness
Scale, and Catherine Knowles-Clark Scale.
77 Nonvalidated scales and other endpoints included the Global Aesthetic Improvement Scale (GAIS),
Numerical Rating Scale, Global Improvement Assessment, Facial Wrinkle Scale, Phaseshift Rapid In
Vivo Measurement of Skin, many ad hoc numeric scales, patient satisfaction, treatment durability,
degree of pain during implantation, and outcomes specific to particular anatomic areas (e.g.,
visibility of hand tendons, lip volume).
Effectiveness
77 Evidence for effectiveness in treating the NLFs was extensive and of high quality (LOE=1b); was
limited but of good quality (LOE=1b−2b) for the lips, oral commissures, glabella, and hands; and
was limited for all other areas (LOE=4).
77 The number of reports, number of subjects enrolled, and highest LOE for each anatomic area are
summarized in Figure 1.
Nasolabial Folds
77 The highest-quality evidence of effectiveness in this analysis was for the nasolabial folds (NLFs),
which included 10 randomized, blinded, split-face, comparative trials (LOE=1b).
77 Treatment of the NLFs concurrently with other areas of the face was represented by fewer
articles, some of which reported studies of good-quality evidence (LOE=1b), although most
represented data quality that was moderate (LOE=2b) or low (LOE=4).
77 Because of the large number of studies in which NLFs were injected, treatment response rates
were evaluated in this analysis.
▪▪ WSRS response rates ranged from 70%–85% for SGP-HA and 63%–75% for LGP-HA.
▪▪ MFWS response rate in a single study (n=149) was 98% for SGP-HA.
▪▪ WAS response rate in a single study (n=105) was 88% for SGP-HA.
▪▪ GAIS response rates were 73%–90% for SGP-HA and 64% for LGP-HA.
Lips, Oral Commissures, Glabella, and Hands
77 Evidence for treating the glabella, lips, and hands included 1 to 2 good-quality (LOE=1b),
randomized, blinded trials for each of these anatomic areas but was more limited than the
evidence for treating the NLFs.
77 SGP-HA has recently received FDA approval for submucosal implantation to achieve lip
augmentation in patients >21 years of age and is the only HA with this indication.
77 Oral commissures were injected in 10 studies, usually concurrent with treatment of other areas.
77 Reports indicated that SGP-HA implantation in the glabella is often combined with injection of
botulinum toxin A, with the intent of limiting mobility and prolonging the augmentation effect.
77 Studies conducted on treatment of the hands included only a small number of patients (n=26).
Other Anatomic Areas
77 At least 1 article described treatment in each of the following areas: nasojugal folds (tear troughs)
and periorbital hollows, upper eyelids, nose, temples, cheeks, marionette lines, and perioral rhytides.
77 The quality of data for effectiveness in these areas was uniformly low (LOE=4).
Safety
77 Common adverse events (AEs) across all anatomic areas were pain, bruising, swelling,
tenderness, redness, and itching.
77 Lumps or irregularities occurred most often in areas where the skin is thin (e.g., nasojugal folds,
periorbital hollows).
77 Serious AEs occurred infrequently (8 events in 8 patients) among the total analysis population
(N≥4605).
▪▪ 7 events were considered unrelated to treatment.
–– 2 patients injected in the NLFs with SGP-HA
–– 2 patients injected in the NLFs with SGP-HA and LGP-HA
–– 2 patients injected in the lips with SGP-HA and 1 injected in the lips with LGP-HA
▪▪ 1 event (mild, transient ischemic attack in a patient injected with SGP-HA in the lips) was
considered probably unrelated to treatment.
Conclusions
77 The effectiveness and safety of small and large gel particle hyaluronic
acid is well established by high-level, randomized, peer-reviewed data
for the nasolabial folds; the evidence base for treatment in the lips, oral
commissures, glabella, and hands is of good quality but more limited.
77 Level 4 data from case reports and series suggest effectiveness in
several other anatomic regions, without major complications for any
treatment area. Additional clinical studies are needed.
Systematic Review of Clinical Trials of
Small and Large Gel Particle Hyaluronic
Acid Injectable Fillers for Aesthetic
Soft-Tissue Augmentation
Joel L. Cohen, M.D.,1
Rhoda S. Narins, M.D.,2
Fredric Brandt, M.D.,3
Steven H. Dayan, M.D., F.A.C.S.,4
Diane B. Nelson, B.S.N., M.P.H.5
1
AboutSkin Dermatology and DermSurgery, Englewood, CO, USA; 2
The Dermatology
Surgery & Laser Center, White Plains, NY, USA; 3
Dermatology Research Institute LLC,
Coral Gables, FL, USA; 4
Chicago Center of Facial Plastic Surgery, Chicago, IL, USA;
5
Medicis Aesthetics Inc., Scottsdale, AZ, USA
References
1. Kablik J, et al. Dermatol Surg. 2009;35(suppl 1):302-312.
2. Sundaram H, et al. Dermatol Surg. 2010;36(suppl 3):1859-1865.
3. Stocks D, et al. J Drugs Dermatol. 2011;10(9):444-449.
4. Rohrich RJ, et al. Plast Reconstr Surg. 2011;127(4 suppl):22S-S.
5. Oxford Centre for Evidence-Based Medicine. Levels of Evidence. Available at: http://www.cebm.net/index.aspx?o=1025.
Accessed October 20, 2011.
Figure 1. Results of Literature Search and Analysis
Glabella
7 reports
n=650
LOE=1b
Nose
2 reports
n=19
LOE=4
Cheeks
3 reports
n=191
LOE=4
Upper eyelids
1 report
n=19
LOE=4
Color Legend
Well established
Limited evidence
Preliminary evidence
Temples
2 reports
n=20
LOE=4
Oral commissures
10 reports
n=1114
LOE=1b
NLFs
32 reports
n=3197
LOE=1b
Nasojugal folds, periorbital hollows
7 reports
n=566
LOE=4
Lips
8 reports
n=1365
LOE=1b
Hands
2 reports
n=26
LOE=1b
Marionette lines,
perioral rhytides
3 reports
n=193
LOE=4
LOE=level of evidence; NLF=nasolabial fold.
Some studies included treatment of several anatomic areas; these studies and their patients are counted in multiple treatment
areas simultaneously. The highest LOE for each treatment area is shown; LOEs ranged from high (1b, representing good-quality
randomized controlled trials) to low (4, e.g., case reports).