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Corneal Collagen Cross-Linking

Policy Number: MP-639

Latest Review Date: March 2022

Category: Medical                                                              


Corneal collagen cross-linking using riboflavin and ultraviolet A, may be considered medically necessary for treatment of progressive keratoconus in patients who have failed conservative treatment (e.g., spectacle correction, rigid contact lens).

Progressive keratoconus is defined as one or more of the following:

  • An increase of 1 diopter (D) in the steepest keratometry value
  • An increase of 1 diopter (D) in regular astigmatism evaluated by subjective manifest refraction
  • A myopic shift (decrease in the spherical equivalent) of 0.50 diopter (D) on subjective manifest refraction
  • A decrease ≥0.1 mm in the back optical zone radius in rigid contact lens wearers where other information was not available.

Corneal collagen cross-linking using riboflavin and ultraviolet A is considered investigational for all other indications.

Complications or later procedures/surgery related to the treatment of corneal ectasia following refractive surgery (e.g. LASIK), which is a benefit exclusion, will not be covered, even if medically necessary.


Corneal collagen cross-linking is a photochemical procedure approved by the Food and Drug Administration (FDA) for the treatment of progressive keratoconus and corneal ectasia. Keratoconus is a dystrophy of the cornea characterized by progressive deformation (steepening) of the cornea while corneal ectasia is keratoconus that occurs after refractive surgery. Both lead to functional loss of vision and need for corneal transplantation.

Treatment of Keratoconus and Ectasia

The initial treatment for keratoconus often consists of hard contact lenses. A variety of keratorefractive procedures have also been attempted, broadly divided into subtractive and additive techniques. Subtractive techniques include photorefractive keratectomy or laser in situ keratomileusis (LASIK), although generally, results of these techniques have been poor. Implantation of intrastromal corneal ring segments is an additive technique in which the implants are intended to reinforce the cornea, prevent further deterioration, and potentially obviate the need for penetrating keratoplasty. Penetrating keratoplasty (i.e., corneal grafting) is the last line of treatment. About 20% of patients with keratoconus will require corneal transplantation. All of these treatments attempt to improve the refractive errors, but are not disease-modifying.

Treatment options for ectasia include intraocular pressure-lowering drugs, and intracorneal ring segments. Frequently, penetrating keratoplasty is required.

None of the currently available treatment options for keratoconus and corneal ectasia halt the progression of disease, and corneal transplantation is the only option available when functional vision can no longer be achieved.

Corneal collagen cross-linking has the potential to slow the progression of disease. It is performed with the photosensitizer riboflavin (vitamin B₂) and ultraviolet A irradiation. There are two protocols for corneal collagen cross-linking:

  1. Epithelium-off corneal collagen cross-linking (also known as “epi-off”): In this method, about eight mm of the central corneal epithelium is removed under topical anesthesia to allow better diffusion of the photosensitizer riboflavin into the stroma. Following de-epithelialization, a solution with riboflavin is applied to the cornea (every one to three minutes for 30 minutes) until the stroma is completely penetrated. The cornea is then irradiated for 30 minutes with ultraviolet A 370 nm, a maximal wavelength for absorption by riboflavin, while the riboflavin continues to be applied. The interaction of riboflavin and UVA causes the formation of reactive oxygen species, leading to additional covalent bonds (cross-linking) between collagen molecules, resulting in stiffening of the cornea. Theoretically, by using a homogeneous light source and absorption by riboflavin, the structures beyond a 400-micron thick stroma (endothelium, anterior chamber, iris, lens, retina) are not exposed to an ultraviolet dose that is above the cytotoxic threshold.
  2. Epithelium-on corneal collagen cross-linking (also known as “epi-on” or transepithelial): In this method, the corneal epithelial surface is left intact (or may be partially disrupted) and a longer riboflavin loading time is needed.

Currently, the only corneal collagen cross-linking treatment approved by the Food and Drug Administration (FDA) is the epithelium-off method. There are no FDA-approved corneal collagen cross-linking treatments using the epithelium-on method. Corneal collagen cross-linking is being evaluated primarily for corneal stabilization in patients with progressive corneal thinning, such as keratoconus and corneal ectasia following refractive surgery. Corneal collagen cross-linking may also have anti-edematous and antimicrobial properties.


This evidence review has been updated regularly with searches of the PubMed database. The most recent literature update was performed through February 11, 2022.

Summary of Evidence

For individuals who have progressive keratoconus who receive corneal collagen cross-linking using riboflavin and ultraviolet A, the evidence includes randomized controlled trials (RCTs), systematic reviews, and nonrandomized studies. Relevant outcomes are change in disease status, functional outcomes, and treatment-related morbidity. Based on RCT evidence used to inform FDA approval, corneal collagen cross-linking was associated significant improvements in corneal curvature score and corrected distance visual acuity and non-significant improvement in uncorrected distance visual acuity compared with sham treatment after one year follow-up. Long-term RCT follow-up is needed. Several non-randomized studies measured visual acuity and other measures with corneal collagen cross-linking. The adverse events associated with corneal collagen cross-linking include corneal opacity (haze), corneal epithelial defects, and other ocular findings. Most adverse events resolved in the first month but continued in a few (1%-6%) patients for six to 12 months. The evidence is sufficient to determine that the technology results in an improvement in the net health outcomes

Practice Guidelines and Position Statements

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

National Institute for Health and Care Excellence

In 2013, the National Institute for Health and Care Excellence (NICE) issued guidance on corneal collagen cross-linking using riboflavin and ultraviolet A, updating its guidance based on a 2009 systematic review of primarily low-quality evidence; review authors declared no financial conflicts of interest. The 2013 guidance stratified recommendations for corneal collagen cross-linking as follows:

“Most of the published evidence on photochemical corneal collagen cross‑linkage using riboflavin and ultraviolet A (UVA) for keratoconus and keratectasia relates to the technique known as ‘epithelium-off corneal collagen cross-linking’. ‘Epithelium‑on (transepithelial) corneal collagen cross-linking’ is a more recent technique and less evidence is available on its safety and efficacy. Either procedure (epithelium‑off or epithelium‑on corneal collagen cross-linking) can be combined with other interventions, and the evidence base for these combination procedures (known as ‘corneal collagen cross-linking plus’) is also limited. Therefore, different recommendations apply to the variants of this procedure, as follows.

1.1 Current evidence on the safety and efficacy of epithelium‑off corneal collagen cross-linking for keratoconus and keratectasia is adequate in quality and quantity. Therefore, this procedure can be used provided that normal arrangements are in place for clinical governance, consent and audit.

1.2 Current evidence on the safety and efficacy of epithelium‑on (transepithelial) corneal collagen cross-linking, and the combination (corneal collagen cross-linking plus) procedures for keratoconus and keratectasia is inadequate in quantity and quality. Therefore, these procedures should only be used with special arrangements for clinical governance, consent and audit or research.”

U.S. Preventive Services Task Force Recommendations

Not applicable.


Corneal Collagen Cross-linking, refractory surgery, LASIK, Keratoconus, Photrexa Viscous®; Avedro, Photrexa®; Avedro, corneal ectasia, CXL, KXL


Epithelium-off corneal cross-linking performed with Photrexa® Drug Formulations, Photrexa® Viscous, Photrexa® and KXL® System is the only cross-linking procedure approved by the FDA.


Coverage is subject to member’s specific benefits.  Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply.

FEP:  Special benefit consideration may apply.  Refer to member’s benefit plan.  FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.


CPT Codes:


Collagen cross-linking of cornea (including removal of the corneal epithelium, when performed, and intraoperative pachymetry when performed)

HCPCS Codes:


Riboflavin 5'-phosphate, ophthalmic solution, up to 3 mL


  1. Avedro Inc. Photorexa Viscous and Photorexa Prescribing Label. 2016; Accessed February 3, 2022.
  2. Badawi AE. Accelerated corneal collagen cross-linking in pediatric keratoconus: One year study. Saudi J Ophthalmol. Jan-Mar 2017; 31(1):11-18.
  3. Caporossi A, Mazzotta C, Baiocchi S, et al. Long-term results of riboflavin ultraviolet a corneal collagen cross-linking for keratoconus in Italy: the Siena Eye Cross Study. Am J Ophthalmol. Apr 2010; 149(4):585-593. PMID 20138607
  4. Center for Drug Evaluation and Research. Application Number 203324Orig2s000. Summary Review. 2015; Accessed February 4, 2022.
  5. Cifariello F, Minicucci M, Di Renzo F, Di Taranto D, Coclite G, Zaccaria S, De Turris S, Costagliola C. Epi-Off versus Epi-On Corneal Collagen Cross-Linking in Keratoconus Patients: A Comparative Study through 2-Year Follow-Up. J Ophthalmol. 2018 Jul 29;2018:4947983. 
  6. Davis LJ, Schechtman KB, Wilson BS, et al. Longitudinal changes in visual acuity in keratoconus. Invest Ophthalmol Vis Sci. Feb 2006; 47(2):489-500.
  7. Hersh PS, Stulting RD, Muller D, et al. United States multicenter clinical trial of corneal collagen crosslinking for keratoconus treatment. Ophthalmology. Sep 2017; 124(9):1259-1270.
  8. Hersh PS, Stulting RD, Muller D, et al. U.S. multicenter clinical trial of corneal collagen crosslinking for treatment of corneal ectasia after refractive surgery. Ophthalmology. Oct 2017;124(10):1475-1484
  9. IOM (Institute of Medicine). 2011. Clinical Practice Guidelines We Can Trust. Washington, DC: The National Academies Press.
  10. Knutsson KA, Paganoni G, Matuska S, et al. Corneal collagen cross-linking in pediatric patients affected by keratoconus. Br J Ophthalmol. Feb 2018; 102(2):248-252.
  11. McAnena L, Doyle F, O'Keefe M. Cross-linking in children with keratoconus: a systematic review and meta-analysis. Acta Ophthalmol. Sep 28 2016.
  12. McMahon TT, Edrington TB, Szczotka-Flynn L, et al. Longitudinal changes in corneal curvature in keratoconus. Cornea. Apr 2006; 25(3):296-305.
  13. National Institute for Health and Care Excellence (NICE). Photochemical corneal collagen cross-linkage using riboflavin and ultraviolet A for keratoconus and keratectasia [IPG466]. 2013; Accessed February 5, 2022.
  14. Padmanabhan P, Rachapalle Reddi S, Rajagopal R, et al. Corneal collagen cross-linking for keratoconus in pediatric patients-long-term results. Cornea. Dec 01 2016.
  15. Papaioannou L, Miligkos M, Papathanassiou M. Corneal collagen cross-linking for infectious keratitis: a systematic review and meta-analysis. Cornea. Jan 2016; 35(1):62-71.
  16. Raiskup F, Theuring A, Pillunat LE, et al. Corneal collagen crosslinking with riboflavin and ultraviolet-A light in progressive keratoconus: ten-year results. J Cataract Refract Surg. Jan 2015; 41(1):41-46.
  17. Raiskup-Wolf F, Hoyer A, Spoerl E, et al. Collagen crosslinking with riboflavin and ultraviolet-A light in keratoconus: long-term results. J Cataract Refract Surg. May 2008; 34(5):796-801.
  18. Toprak I, Yaylali V, Yildirim C. Visual, topographic, and pachymetric effects of pediatric corneal collagen cross-linking. J Pediatr Ophthalmol Strabismus. Mar 1 2017; 54(2):84-89.
  19. Wittig-Silva C, Whiting M, Lamoureux E, et al. A randomized controlled trial of corneal collagen cross-linking in progressive keratoconus: preliminary results. J Refract Surg. Sep 2008; 24(7):S720-725. PMID 18811118
  20. Wittig-Silva C, Chan E, Islam FM, et al. A randomized, controlled trial of corneal collagen cross-linking in progressive keratoconus: three-year results. Ophthalmology. Apr 2014; 121(4):812-821.


Medical Policy Panel, March 2017

Medical Policy Group, April 2017 (6): New policy adopted from association

Medical Policy Administration Committee, May 2017

Available for comment April 28 through June 11, 2017

Medical Policy Panel, March 2018

Medical Policy Group, March 2018: (6) Updates to Key Points and References.

Medical Policy Group, June 2018: (6) Update to policy statement to include “e.g.” by LASIK.

Medical Policy Group, December 2018:  2019 Annual Coding Update:  Added HCPCS code J2787 to Current coding section.

Medical Policy Panel, March 2019

Medical Policy Group, April 2019 (6): Updates to Key Points and References. No change to policy statement.

Medical Policy Panel, March 2020

Medical Policy Group, March 2020 (6): Updates to Key Points.

Medical Policy Panel, March 2021

Medical Policy Group, March 2021 (9): 2021 Updates to Key Points, Description, References. Policy statement updated to remove effective for dates of service prior to April 26, 2017 information, and “not medically necessary”, no change to policy intent.

Medical Policy Panel, March 2022

Medical Policy Group, March 2022 (9): 2022 Updates to Key Points, Description, Approved By Governing Bodies, References. No change to policy statement.

Medical Policy Group, June 2022 (9): Quarterly coding update. CPT code 0402T revised to include "epi on" as well as "epi off" by adding the verbiage "when performed" to code description.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.