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    Comparing CXL Protocols

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    Which of the two main corneal cross-linking (CXL) techniques for corneal ectasia is safer and more efficacious? A team of Canadian researchers who waded into this debate came up with mixed results.1 Their meta-analysis found that while transepithelial CXL is significantly safer than conventional epitheli­um-off CXL, it remains inferior in its ability to reduce corneal steepness and arrest disease. Nonetheless, the researchers found equivalent visual and refractive out­comes between the two approaches.

    “This creates a conundrum, as there is no clear way forward,” said Siddharth Nath, MD, PhD, at McGill Uni­versity in Montreal.

    Comparing CXL Protocols

    Pros and cons. The researchers identified 12 ran­domized controlled studies, totaling 966 eyes.

    Efficacy. The primary outcome of this meta-analysis was change in maximal keratometry (Kmax) 12 months following CXL. In the transepithelial group, Kmax de­creased from a preoperative baseline of 52.38 D to 52.32 D, compared to a decrease from 52.80 D to 52.26 D in the epithelium-off group.

    In addition, the researchers found that disease pro­gression, defined as an increase of ≥1.0 D in Kmax at 12 months, was significantly higher in transepithelial CXL eyes (7%) than epithelium-off eyes (2%).

    Safety. The rate of significant complications (corneal melt, persistent epithelial defects, and visually signifi­cant nonresolving haze) was 4% with conventional CXL, versus 2% with transepithelial CXL.

    Visual outcomes. No significant differences were observed in changes to corrected and uncorrected visual acuity. In the transepithelial group, uncorrected distance visual acuity (UDVA) improved from 0.85 Log­MAR units at baseline to 0.70 at 12 months following CXL; UDVA in the epithelium-off eyes improved from 0.80 at baseline to 0.64 at 12 months. For corrected distance VA, those pre- and posttreatment measure­ments were 0.30 and 0.22 in transepithelial eyes and 0.28 and 0.18 in the epithelium-off group.

    Further study may narrow the gap. The inferior efficacy of transepithelial CXL may be attributed to factors such as insufficient penetra­tion of riboflavin into the stroma, the authors noted. This suggests a potential for refining the protocol to achieve an approach that is both safe and more effective.

    “There certainly needs to be a discussion around this finding and how it might impact protocol selection. The reason we maintain that transepithelial CXL is inferior in efficacy to conventional CXL is that it is also associ­ated with increased rates of disease progression,” Dr. Nath said. “More rigorous trials may find the two CXL protocols even closer in efficacy than currently reported.”

    —Miriam Karmel


    1 Nath S et al. Ophthalmology. Published online Dec. 28, 2020.


    Relevant financial disclosures—Dr. Nath: None.

    For full disclosures and the disclosure key, see below.

    Full Financial Disclosures

    Dr. Antoszyk Genentech: C,S; Jaeb Center for Health Research: C; No­vartis: C; Opthea: C; Regeneron: C; Roche: C,S.

    Dr. Fekrat None.

    Dr. Grewal None.

    Dr. Nath None.

    Dr. Yiu Alimera: C; Allergan: C; Carl Zeiss: C; Clearside Biomed­ical: C,S; Genentech: C,S; Iridex: C,S; Intergalactic Thera­peutics: C; Topcon: C; Verily: C.

    Disclosure Category



    Consultant/Advisor C Consultant fee, paid advisory boards, or fees for attending a meeting.
    Employee E Employed by a commercial company.
    Speakers bureau L Lecture fees or honoraria, travel fees or reimbursements when speaking at the invitation of a commercial company.
    Equity owner O Equity ownership/stock options in publicly or privately traded firms, excluding mutual funds.
    Patents/Royalty P Patents and/or royalties for intellectual property.
    Grant support S Grant support or other financial support to the investigator from all sources, including research support from government agencies (e.g., NIH), foundations, device manufacturers, and/or pharmaceutical companies.


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