Effectiveness of Low Doses of Hyaluronidase to Remove Hyaluronic Acid Filler Nodules: A Randomized Clinical Trial

Abstract

Importance: Although hyaluronidase is known to remove hyaluronic acid fillers, use of low doses has not been well studied.

Objective: To assess the effectiveness and dose-related effect of small quantities of hyaluronidase to treat hyaluronic acid filler nodules.

Design, setting, and participants: Split-arm, parallel-group, randomized clinical trial at an urban academic center. Participants were 9 healthy women. Recruitment and follow-up occurred from February 2013 to March 2014; data analysis occurred from February to July 2016.

Interventions: Each participant received aliquots (buttons) of either of 2 types of hyaluronic acid fillers into bilateral upper inner arms, respectively. At 1, 2, and 3 weeks each button was treated with a constant volume (0.1 mL) of variable-dose hyaluronidase (1.5, 3.0, or 9.0 U per 0.1 mL) or saline control.

Main outcomes and measures: Both a blinded dermatologist and the participant independently assessed detectability.

Results: Seventy-two treatment sites on 9 women (mean [SD] age, 45.8 [15.7] years) received all interventions and were analyzed. There was a significant difference in physician rater assessment between saline and hyaluronidase at 4 weeks (visual detection: mean difference = 1.15; 95% CI, 0.46-1.80; P < .001; palpability: mean difference = 1.22; 95% CI, 0.61-1.83; P < .001) and 4 months (visual detection: mean difference = 0.77; 95% CI, 0.33-1.26; P = .001; palpability: mean difference = 0.82; 95% CI, 0.38-1.25; P < .001) that was mirrored by participant self-assessment at 4 weeks (visual detection: mean difference = 0.87; 95% CI, 0.26-1.48; P = .006; palpability: mean difference = 1.59; 95% CI, 1.41-1.77; P < .001) and 4 months (visual detection: mean difference = 1.31; 95% CI, 1.09-1.53; P < .001; palpability: mean difference = 1.52; 95% CI, 1.03-2.01; P < .001), and hyaluronidase was associated with greater resolution of buttons compared with normal saline. The 9.0-unit hyaluronidase injection sites were significantly less palpable than the 1.5-unit sites at both 4 weeks (mean difference = 0.50; 95% CI, 0.01-.99; P = .045) and 4 months (mean difference = 0.47; 95% CI, 0.14-0.81; P = .007). Dose dependence was more notable for Restylane-L.

Conclusions and relevance: Although very small doses of hyaluronidase can remove hyaluronic acid fillers from patient skin, slightly higher doses often result in more rapid resolution.

Trial registration: clinicaltrials.gov Identifier: NCT01722916.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Alam is employed at Northwestern University. Dr Alam has been a consultant for Amway and Leo Pharma, both unrelated to this research. Grants: Northwestern University has a clinical trials unit that receives grants from very many corporate and governmental entities to perform clinical research. Dr Alam has been principal investigator on studies funded in part by Allergan, Medicis, Bioform, and Ulthera. In all cases, grants and gifts in kind have been provided to Northwestern University and not Dr Alam directly, and Dr Alam has not received any salary support from these grants. Dr Alam receives royalties from Elsevier for technical books he has edited. No other disclosures are reported.

Figures

Figure 1.. CONSORT Flowchart

Figure 2.. Dermatologist Ratings for Perceptibility of Hyaluronic Acid Filler Buttons

A, Restylane-L (Galderma Laboratories), normal saline vs 9.0 U, significant rater difference at all follow-up visits; 1.5 vs 9.0 U, significant difference at week 3. B, Restylane-L, normal saline vs 9.0 U, significant rater difference at all follow-up visits; 1.5 vs 9.0 U, significant difference at all follow-up visits; 3.0 vs 9.0 U, significant difference at week 4. C, Juvéderm Ultra XC (Allergan Inc), normal saline vs 9.0 U, significant rater difference at weeks 2, 3, and 4; normal saline vs 1.5 U, significant difference at weeks 2, 3, and 4; normal saline vs 3.0 U, significant difference at weeks 3 and 4. D, Juvéderm Ultra XC, normal saline vs 9.0 U, significant rater difference at weeks 3, 4, and month 4; normal saline vs 1.5 U, significant difference at weeks 3 and 4; normal saline vs 3.0 U, significant difference at weeks 3 and 4; 1.5 U vs 9.0 U, significant difference at month 4. Data markers indicate dose of hyaluronidase, and error bars indicate standard error of the mean. Differences were statistically significant at P < .05.

Figure 3.. Participant Ratings for Perceptibility of Hyaluronic Acid Filler Buttons

A, Restylane-L (Galderma Laboratories), normal saline vs 9.0 U, significant rater difference at month 4. B, Restylane-L, normal saline vs 9.0 U, significant rater difference at all follow-up visits; normal saline vs 1.5 U, significant difference at weeks 3 and 4; normal saline vs 3 U, significant difference at weeks 2, 3, and month 4. C, Juvéderm Ultra XC (Allergan Inc), normal saline vs 9.0 U, significant rater difference at weeks 2, 4, and month 4; normal saline vs 1.5 U, significant difference at weeks 2, 4, and month 4; normal saline vs 3.0 U, significant difference at week 3 and month 4. D, Juvéderm Ultra XC, normal saline vs 9.0 U, significant rater difference at all follow-up visits; normal saline vs 1.5 U, significant difference at all follow-up visits; normal saline vs 3.0 U, significant difference at all follow-up visits. Data markers indicate dose of hyaluronidase, and error bars indicate standard error of the mean. Differences were statistically significant at P < .05.