Corneal collagen cross-linking epithelium-on vs. epithelium-off: a systematic review and meta-analysis.

Background: The purpose of the study was to determine the advantages and disadvantages of epi-on corneal cross-linking (CXL) techniques compared with standard epi-off CXL.

Methods: We searched MEDLINE and EMBASE for randomized controlled trials (RCTs) and non-randomized studies of interventions (NRSIs) and we evaluated the selected papers according to the Cochrane risk of bias tool. We considered, as primary outcomes, average Kmax flattening, changes in uncorrected and corrected distance visual acuity (UDVA and CDVA); as secondary outcomes, we considered changes in pachymetry values and endothelial cell density (ECD). We also investigated adverse events related to the treatments and treatment failure. Meta-analysis was conducted with a fixed or random-effects model using weighted mean difference (MD) with 95% confidence interval (CI) as the effect size.

Results: A total of 15 studies were included and among these 15 trials, 9 were RCTs and 6 were NRSIs, but only 4 studies showed no high risk of bias and were included in this meta-analysis. Our analysis revealed significant postoperative differences in CDVA (MD = 0.07; 95% CI 0.04 to 0.10; P < 0.001), and no significative differences in UDVA, Kmax, central corneal thickness (CCT) and ECD (P > 0.05). Epi-on CXL protocol was found to be significantly less prompt to have risks of delay in epithelial healing (P = 0.035) and persistent stromal haze (P = 0.026).

Conclusion: Epi-on CXL is as effective as epi-off CXL. Except for a higher significant improvement in CDVA with current epi-on protocols, our meta-analysis demonstrates that epi-on and epi-off CXL have comparable effects on visual, topographic, pachymetric, and endothelial parameters. Epi-on CXL has clinical advantages in terms of comfort and avoidance of complications as it reduces the risk of developing delay in epithelial healing and persistent stromal haze.