Corneal Crosslinking: Taking a Closer Look at the Data That Convinced the FDA

United States Multicenter Clinical Trial of Corneal Collagen Crosslinking for Keratoconus Treatment

Hersh PS, Stulting RD, Muller D, Durrie DS, Rajpal RK; United States Crosslinking Study Group
Ophthalmology. 2017 May 7. [Epub ahead of print]

Study Summary

Corneal collagen crosslinking (CXL), a procedure to strengthen the cornea originally devised to treat patients with keratoconus, is now also used to treat post-refractive surgery ectasia. It was developed in Europe over 15 years ago and has been in widespread use around the world for at least the past 5 years. It was approved by the US Food and Drug Administration (FDA) in April 2016.

Hersh and colleagues report on the results of the trial used to obtain the FDA approval, which included patients aged 14 years or older with progressive keratoconus and thinnest corneal thickness greater than 300 microns, measured by Pentacam. The technique entailed removing the epithelium, placing riboflavin for 30 minutes, and checking the pachymetry. When the pachymetry was less than 400 microns (which was probably fairly common, as the inclusion criteria allowed corneal thicknesses down to 300 microns prior to epithelial removal), additional hypotonic riboflavin was placed until the thickness reached at least 400 microns. UVA light was then applied for 30 minutes.

Patients were randomized to treatment or sham groups, with the latter receiving 30 minutes of riboflavin drops but no epithelial removal and no UVA light. All patients were followed for 3 months, at which time the sham eyes could cross over into the treatment group. Almost all sham eyes crossed over, with only 2 of 103 control eyes available at 1 year.

The results were good and in line with those published globally over the past decade, largely demonstrating stability in the treatment group and continued progression in the control group.

Viewpoint

There were several interesting aspects to these results.

About 6% of treated eyes had maximal keratometry steepening of ≥ 2 diopters at 1 year and should probably be considered treatment failures. Of course, they might have progressed much more had they not undergone CXL; we will never know.

The authors found only one independent predictor of flattening of maximal keratometry, with eyes with a preoperative maximal keratometry of ≥ 55 diopters 5.4 times more likely to end up with a maximal keratometry flattening of ≥ 2 diopters than eyes with flatter corneas preoperatively. They could not identify any independent predictors of significant corneal steepening (progression).

Surgeons and patients should be aware that they found an increase in maximal keratometry in treated eyes at 1 month, which returned to near baseline at 3 months but showed flattening at 6 and 12 months.

Similarly, best corrected vision worsened slightly at 1 month, but then improved compared with baseline from 3 to 12 months. This early worsening and subsequent return to baseline or even improvement in keratometry and vision has been my experience, both prior to FDA approval several years ago (as part of the ACOS-Avedro study) and since FDA approval.

What intrigued me the most about this study was that it was performed with the UV-X system from IROC Science AG, based in Zurich, Switzerland, although the FDA approved the KXL system from Avedro Inc, in the United States. In the article's "discussion" section, the authors state, "Although the UV-X system was used as the ultraviolet light source in this study, FDA specifically approved CXL using the KXL system. However, there is no noticeable difference in the ultraviolet wavelength or energy delivered or in other attributes of the actual ultraviolet light between the systems." Of note, the authors provide no references or evidence for this statement in the article.

Abstract

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