Long-term Safety and Effectiveness of Cold-Crosslinked Hyaluronic Acid Fillers: Multicenter, Randomized, Controlled, Double-Blind Study.

Summary

In a multicenter double-blind randomized split-face trial (N=140), cold-crosslinked HA fillers (EVLF, EVLS) achieved noninferiority and statistical superiority versus Restylane-L on WSRS at 6 months, with EVLF maintaining superiority through 12 months. Patient-reported outcomes (FACE-Q) improved significantly at all time points and treatments were well tolerated.

Key Findings

• Primary endpoint: cold-crosslinked fillers achieved noninferiority and statistical superiority versus Restylane-L on WSRS at Month 6.
• EVLF showed statistically superior WSRS improvements at all visits through 12 months; EVLS at 6 and 9 months.
• FACE-Q scores improved significantly from baseline (P < .0001) at all time points; treatments were well tolerated.

Clinical Implications

Cold-crosslinked HA fillers can be considered first-line options for nasolabial folds, offering year-long efficacy and favorable patient satisfaction. Clinicians can counsel patients on durability and safety compared with an established comparator.

Limitations

• Single comparator (Restylane-L) and single indication (nasolabial folds) limit generalizability
• Optional retreatment at 12 months and lack of data beyond 12–15 months constrain long-term conclusions

Future Directions

Head-to-head trials across additional facial indications and comparators, longer-term safety/immunogenicity surveillance, and mechanistic studies on cold-crosslinking properties.