Corneal Collagen Cross-linking

Number 9.03.28

Effective Date June 17, 2015

Revision Date(s) 06/09/15; 06/09/14; 05/13/13

Replaces N/A


Corneal collagen cross-linking is considered investigational for all indications.

Related Policies



Policy Guidelines


There are no specific CPT codes for this treatment, it may be reported using:



Unlisted procedure, anterior segment of eye


Corneal collagen cross-linking (CXL) is a photochemical procedure that is being evaluated as a method to stabilize the cornea in patients with progressive keratectasia such as keratoconus and pellucid marginal degeneration. CXL may also have anti-edematous and antimicrobial properties and has been evaluated for the treatment of corneal edema, bullous keratopathy, and infectious keratitis.


Corneal CXL is performed with the photosensitizer riboflavin (vitamin B2) and ultraviolet-A (UVA) irradiation. A common CXL protocol removes about 8 mm of the central corneal epithelium 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 1-3 minutes for 30 minutes) until the stroma is completely penetrated. The cornea is then irradiated for 30 minutes with 370 nm UVA, a maximal wavelength for absorption by riboflavin, together with the continued application of riboflavin. The interaction of riboflavin and UVA causes the formation of reactive oxygen species, leading to additional covalent bonds (cross-linking) between collagen molecules that results 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 a UV dose that is above the cytotoxic threshold.

CXL is being evaluated primarily for corneal stabilization in patients with progressive corneal thinning, such as keratoconus. CXL may also have anti-edematous and antimicrobial properties.

Keratoconus is a bilateral dystrophy that is characterized by progressive ectasia (paracentral steepening and stromal thinning) that impairs visual acuity. While frequently diagnosed at a young age, The progression of keratoconus is variable. Initial treatment 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 LASIK, but in general, results of these techniques have been poor. Implantation of intrastromal corneal ring segments (see Related Policies) 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. In contrast, CXL has the potential to slow the progression of disease.

Pellucid marginal degeneration is a noninflammatory progressive degenerative disease, typically characterized by bilateral peripheral thinning (ectasia) of the inferior cornea. Deterioration of visual function results from the irregular astigmatism induced by asymmetric distortion of the cornea, and visual acuity typically cannot be restored by using spherocylindrical lenses. Rigid gas permeable contact lenses may be used to treat pellucid marginal degeneration. Intrastromal ring segment implantation, crescentic lamellar keratoplasty, penetrating keratoplasty, and corneal wedge excision have also been proposed.

Regulatory Status

No UVA devices have received clearance or premarket approval for the treatment of keratoconus in the U.S.

A search of online site shows ongoing Phase III safety and efficacy trials of UV-A Illumination Systems by Topcon Medical (VEGA) and Avedro Inc. (KXL or UV-X). (See additional information about clinical trials later in this policy.)

The U.S. Food and Drug Administration (FDA) has granted Avedro Inc. a priority review of their new drug application (NDA) for the riboflavin ophthalmic solution/KXL II™ system as an orphan drug (<200,000 individuals affected in the U.S.). If approved, Avedro would have 7 years of market exclusivity in the U.S.

On February 24, 2015, an FDA advisory committee recommended approval for Avedro’s NDA for riboflavin ophthalmic solutions (Photrexa™) with ultraviolet UVA irradiation for corneal collagen cross-linking to treat progressive keratoconus and corneal ectasia.

The KXL II™ system is currently approved for use in Europe.


Medical policies are systematically developed guidelines that serve as a resource for Company staff when determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to the limits and conditions of the member benefit plan. Members and their providers should consult the member benefit booklet or contact a customer service representative to determine whether there are any benefit limitations applicable to this service or supply. This medical policy does not apply to Medicare Advantage.

Benefit Application



This policy was created in 2012 and updated periodically using the MEDLINE database. The most recent literature update was performed through February 25, 2015.

Natural History of Keratoconus

The Collaborative Longitudinal Evaluation of Keratoconus (CLEK) study is a multi-center long-term observational study of the natural history of keratoconus. Two reports were published from the CLEK study in 2006 that showed slow changes over 7 years of follow-up. (1, 2) Davis et al. reported changes in high- and low-contrast visual acuity from 953 patients (1,855 eyes). (1) Over a period of 7 years, there was a decrease of 2 high- and 4 low-contrast letters. High-contrast visual acuity decreases of 10 or more letters occurred in 19.0% of patients; low-contrast visual acuity decreases of 10 or more letters occurred in 30.8% of patients. McMahon et al. reported longitudinal changes in corneal curvature over 8 years of follow-up in 1,032 patients. (2) The slope for First Definite Apical Clearance Lens (FDACL) was 0.18 diopters (D) per year, and the slope for flatter keratometric reading (Flat K) was 0.20 D per year. These translated into mean increases of 1.44 D in FDACL and 1.6 D in Flat K during the 8-year follow-up period. Close to 25% of patients had projected increases of 3 D or more in FDACL, while 24% had projected increases of 3 D or more in Flat K.

Corneal Collagen Cross-Linking

Evidence on whether corneal collagen cross-linking (CXL) improves health outcomes for patients with progressive keratoconus includes 5 randomized controlled trials (RCTs), 3 of which were regulated by FDA under a new drug application (NDA). In addition, there are a number of prospective controlled studies as well as uncontrolled trials that report on longer-term outcomes of the procedure. (3) The main health outcome for CXL treatment is improvement, or stabilization, of visual acuity. Other outcomes commonly reported in trials of CXL include physiologic measures, such as the steepness of the corneal curvature measured by maximum keratometry (K-max) and/or the manifest refraction spherical equivalent (MRSE). These are intermediate outcomes that may corroborate whether improvements in visual acuity correlate with physiologic changes.

Randomized Controlled Trials

Data submitted to FDA under the NDA for riboflavin ophthalmic solution/KXL® came from 3 RCTs with a total sample size of 640 patients.4 Results from one of the trials were published in 2011 and 2012. (5,6) Each of the Phase III trials was a parallel group, open-label trial in patients with keratoconus or corneal ectasia due to LASIK or photorefractive keratectomy. Sham-control eyes were treated with a topical anesthetic and riboflavin solution (1 drop every 2 minutes for 30 minutes) but did not undergo epithelial debridement or have the ultraviolet A (UVA) light source turned on. The primary outcome was a 1 D difference in the mean change in K-max (progression of steepening) between the CXL and control groups at 12 months. Control patients could cross over to CXL at 3 months, and missing data were analyzed by last observation carried forward (LOCF). Ninety-nine percent of control patients had crossed over by 12 months. LOCF analysis is a conservative method of analysis in this situation, because it reduces the expected worsening over time in untreated patients. In the pooled analysis of patients with keratoconus, steepening worsened by 1.0 D in the control group and improved by 1.6 D in the CXL group, for a total difference between groups of 2.6 D. CXL resulted in either stabilization or improvement in K-max in 72% of keratoconus patients. In the sham control group, there was no statistically significant change in K-max. The mean improvement in best-corrected visual acuity (BCVA) was 5.6 letters following CXL compared with 2.0 letters for controls (p=0.009). Although this difference is not typically considered clinically significant, it is limited by the use of 3-month data for many of the patients in the control group, which would minimize between-group differences over time. The proportion of patients who had a clinically significant 3-line or greater improvement in BCVA was 19.4% for the CXL-treated patients and 8.1% for controls. Treatment-related adverse events were generally transient, mild, and expected based on the epithelial debridement and corneal remodeling.

Wittig-Silva et al. reported the first RCT of corneal CXL in 2008. (7) Three-year results were published in 2014. (8) Recruitment for the trial was completed in 2009 with 50 eyes randomized to CXL and 50 randomized to untreated control. To be eligible for enrollment, clear evidence of progression of ectasia over the preceding 6 to 12 months was required. Progression was confirmed if at least one of the following criteria were met: an increase of at least 1.00 D in the steepest simulated keratometry reading (K-max); an increase in astigmatism determined by manifest subjective refraction of at least 1.00 D; an increase of 0.50 D in MRSE; or a 0.1 mm or more decrease in back optic zone radius of the best fitting contact lens. At the time of analysis for the 2008 report, 20 eyes had reached 1-year follow-up.

The 3-year results included 46 CXL and 48 control eyes. LOCF was used for 26 eyes, including 17 eyes from the control group with progressive disease that underwent compassionate use CXL or corneal transplantation. In the CXL group, there was a flattening of K-max by -1.03 D, compared with an increase in K-max of 1.75 in the control group. One eye in the CXL group progressed by more than 2.0 D, compared with 19 eyes in the control group. Uncorrected visual acuity (UCVA) and BCVA improved in the CXL-treated eyes at 1, 2, and 3 years. In control eyes, UCVA was significantly reduced at 36 months and there was a trend of a decrease in BCVA (p=0.10). The difference between groups in UCVA was statistically significant. Follow-up is continuing through 5 years.

In 2012, Renesto et al. reported results of a randomized trial that compared CXL versus 1 month of riboflavin eye drops in 39 eyes of 31 patients with keratoconus. (9) After 3 months, all patients received intrastromal corneal ring segments (ICRS). Patients were evaluated at 1 and 3 months after treatment with CXL or riboflavin, and then at 1, 3, 6, 12, and 24 months after ICRS insertion. There was no significant difference between the two groups for UCVA, BCVA, or in 3 topographic parameters (flattest-K, steepest K, and average keratometry) throughout the 24-month follow-up.

Uncontrolled Studies

Longer-term follow-up is being reported from Europe, where the procedure has been performed for a greater number of years. Indications for treatment typically include progression of steepening (increase in K-max by at least 1 D in 1 year), deteriorating visual acuity, or the need for new contact lens-fitting more than once in 2 years. The largest and longest series to date are described next.

In 2008, Raiskup-Wolfe et al. reported outcomes of 241 eyes (130 patients) treated with CXL, with a minimum of 6 months of follow-up. (10) This was of a total of 488 eyes (272 patients) with progressive keratoconus and a corneal thickness of at least 400 microns treated at their center in Germany. Follow-up examinations were performed at 1, 6, and 12 months, and then annually. Mean follow-up was 26 months with a range of 12 months (n=142) to 6 years (n=5). In the first year (n=142), steepening (K-max) improved or remained stable in 86% of eyes, and BCVA improved by at least 1 line in 53% of the eyes. Three years after treatment (n=33), K-max improved by a mean of 2.57 D in 67% of eyes while BCVA improved by at least 1 line in 58% of eyes. In 2015, the same group published 10-year follow-up of CXL treatment in 34 eyes (24 patients) with progressive keratoconus. (11) Mean patient age at the time of treatment was 28 years (range, 14-42). Corneal steepening improved slightly between baseline and 10-year follow-up (p<0.001), while corrected distance visual acuity improved by 0.14 logMAR (p=0.002). Two eyes had repeat CXL, one at 5 years and one at 10 years, without adverse sequelae. One of the 34 eyes treated developed a permanent corneal scar. These studies are limited by the retrospective nature and the small number of cases with extended follow-up.

A 2010 publication from the Siena Eye Cross Study reported a 52-month mean follow-up (range, 48-60) on their first 44 keratoconic eyes treated with CXL. (12) Follow-up evaluations were performed at 1, 2, 3, 6, 12, 24, 36, 48, and 60 months after CXL. Topographic analysis showed a mean K reading reduction of -1.96 D after 1 year, -2.12 D after 2 years, -2.24 D after 3 years, and -2.26 D after 4 years of follow-up. By comparison, in fellow eyes untreated for the first 24 months, the mean K value increased by 1.2 D at 1 year and 2.2 D at 2 years. In treated eyes, UCVA improved by a mean of 2.41 lines after 12 months, 2.75 lines after 24 months, 2.80 lines after 36 months, and 2.85 lines after 48 months. There was no significant decrease in endothelial cell density, central corneal thickness, or intraocular pressure over follow-up. Temporary adverse effects included stromal edema in the first 30 days (70% of patients) and temporary haze (9.8% of patients). No persistent adverse effects were observed.

A 2012 publication from the Siena CXL Pediatrics trial reported 12- to 36 -month follow-up after CXL in 152 patients aged 18 years or younger with keratoconus progression. (13) Visual acuity increased by an average of 0.15 Snellen lines, whereas a clinically relevant change is generally considered to be 2 Snellen lines.

One of the oldest reports is from the French National Reference Center for Keratoconus in 2011. (14) Of 142 eyes enrolled in the study, 6-month follow-up was available for 104 (73%), and 12-month follow-up was available for 64 (45%). At 12 months after treatment, the BCVA had stabilized in 48% of eyes, improved in 40%, and decreased in 12%. Keratoconus progression had stopped in 69%, and K-max had decreased by more than 2.0 D in 21% of eyes. There was a 7% complication rate in the total sample, with 5 eyes (3.5% of 142 or 7.8% of 64) losing more than 2 Snellen lines of visual acuity. This retrospective study is limited by the low proportion of patients available at 12-month follow-up.

Adverse Events

Reported adverse events are relatively uncommon, but precise rates of adverse events are not available because of the lack of large studies with long-term follow-up. Adverse events reported to date include corneal endothelial damage, stromal haze, corneal melt, keratitis, gaping of corneal incisions, and corneal scarring. (15-17)

Ongoing and Unpublished Clinical Trials

A search of in March 2015 identified over 30 ongoing trials on CXL. Some trials likely to influence this policy are listed in Table 1.

Table 1. Summary of Key Trials


Trial Name

Planned Enrollment

Completion Date




A Randomized, Controlled Study of the Vedera™ KXS Microwave System With Corneal Collagen Cross-Linking Compared With Corneal Collagen Cross-Linking Alone for Eyes With Keratoconus


Aug 2015


A Multi-Center, Randomized, Controlled Evaluation of the Safety and Efficacy of the KXL System With VibeX (Riboflavin Ophthalmic Solution) for Corneal Collagen Cross-Linking in Eyes With Keratoconus or Corneal Ectasia After Refractive Surgery


Jan 2016


A Multi-Center, Randomized, Placebo-Controlled Evaluation of the Safety and Efficacy of the KXL System With VibeX (Riboflavin Ophthalmic Solution) for Corneal Collagen Cross-Linking in Eyes With Keratoconus


Mar 2016


A Multi-Center, Randomized, Placebo-Controlled Evaluation of the Safety and Efficacy of the KXL System With VibeX (Riboflavin Ophthalmic Solution) for Corneal Collagen Cross-Linking in Eyes With Keratoconus


Dec 2016


Collagen Crosslinking for Keratoconus - a Randomized Controlled Clinical Trial


May 2017


German Corneal Cross-Linking Registry


Nov 2017

NCT: national clinical trial.

a Denotes industry-sponsored or cosponsored trial.

Clinical Input Received From Physician Specialty Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

2012 Input

In response to requests, input was received from 1 physician specialty society and 1 academic medical center (2 reviewers) while this policy was under review in 2012. The input from all reviewers was mixed, noting the limited literature and lack of FDA approval for this procedure, although there are ongoing FDA-regulated clinical trials. The reviewers also commented on the lack of alternatives to slow the progression of disease and that data indicate that the procedure is safe and effective enough to offer to patients with adequate informed consent under an investigational protocol.

Summary of Evidence

There is evidence from randomized controlled trials (RCTs), including several pivotal trials, that CXL leads to short-term improvements in corneal steepening and visual acuity compared with untreated eyes, and results from 1 trial have reported that benefits are maintained at 2 to 3 years. From these RCTs, one can conclude that CXL is able to reduce, and in some cases reverse, the corneal steepening that leads to a reduction in visual acuity in the short-term. There is greater uncertainty about the long-term outcomes of CXL for the treatment of keratoconus. Some retrospective studies report positive outcomes at out to 10 years, although these reports are limited by the small sample size at long-term follow-up and limited information on the entire population of patients treated with CXL during the same time period. There is a need for prospective studies with larger numbers of patients that are followed over many years to determine whether CXL improves longer-term outcomes. Several trials are ongoing, and results from these other trials are expected soon. Longer-term outcomes from large cohorts will also be useful to evaluate potential long-term complications of this new treatment approach. Although one device is currently under U.S. Food and Drug Administration (FDA) review, no CXL devices have received FDA approval at this time.

Practice Guidelines and Position Statements

National Institute for Health and Care Excellence (NICE)

In 2013 the National Institute for Health and Care Excellence issued an Interventional Procedure Guideline (IPG 466) (18) that replaced the 2009 IPG 320. The new IPG now stratifies their recommendations for corneal CXL as follows:

“Most of the published evidence on photochemical corneal collagen cross linkage (CXL) using riboflavin and ultraviolet A (UVA) for keratoconus and keratectasia relates to the technique known as 'epithelium -off' CXL'. 'Epithelium on (transepithelial) CXL' is a more recent technique and less evidence is available on its safety and efficacy. Either procedure (epithelium off or epithelium on CXL) can be combined with other interventions, and the evidence base for these combination procedures (known as 'CXL -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 CXL 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) CXL, and the combination (CXL -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.”

Information on corneal cross-linking and ongoing trials is provided by the National Keratoconus Foundation.(19)

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.


  1. 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. PMID 16431941
  2. McMahon TT, Edrington TB, Szczotka-Flynn L, et al. Longitudinal changes in corneal curvature in keratoconus. Cornea. Apr 2006; 25(3):296-305. PMID 16633030
  3. Chunyu T, Xiujun P, Zhengjun F, et al. Corneal collagen cross-linking in keratoconus: a systematic review and meta-analysis. Sci Rep. 2014;4:5652. PMID 25007895
  4. U.S. Food and Drug Administration. Briefing package: Riboflavin opthalmic solution/KXL system for the treatment of progressive keratoconus or corneal ectasia following refractive surgery. 2015; Accessed May, 2015.
  5. Hersh PS, Greenstein SA, Fry KL. Corneal collagen crosslinking for keratoconus and corneal ectasia: One-year results. J Cataract Refract Surg. Jan 2011; 37(1):149-160. PMID 21183110
  6. Brooks NO, Greenstein S, Fry K, et al. Patient subjective visual function after corneal collagen crosslinking for keratoconus and corneal ectasia. J Cataract Refract Surg. Apr 2012; 38(4):615-619. PMID 22342006
  7. 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
  8. 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. PMID 24393351
  9. Renesto Ada C, Barros Jde N, Campos M. Impression cytologic analysis after corneal collagen cross-linking using riboflavin and ultraviolet-A light in the treatment of keratoconus. Cornea. Oct 2010; 29(10):1139-1144. PMID 20622670
  10. 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. PMID 18471635
  11. 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. PMID 25532633
  12. 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
  13. Caporossi A, Mazzotta C, Baiocchi S, et al. Riboflavin-UVA-induced corneal collagen cross-linking in pediatric patients. Cornea. Mar 2012;31(3):227-231. PMID 22420024
  14. Asri D, Touboul D, Fournie P, et al. Corneal collagen crosslinking in progressive keratoconus: multicenter results from the French National Reference Center for Keratoconus. J Cataract Refract Surg. Dec 2011; 37(12):2137-2143. PMID 22108109
  15. Gkika M, Labiris G, Kozobolis V. Corneal collagen cross-linking using riboflavin and ultraviolet-A irradiation: a review of clinical and experimental studies. Int Ophthalmol. Aug 2011; 31(4):309-319. PMID 21847678
  16. Gokhale NS. Corneal endothelial damage after collagen cross-linking treatment. Cornea. Dec 2011; 30(12):1495-1498. PMID 22001813
  17. Abad JC, Vargas A. Gaping of radial and transverse corneal incisions occurring early after CXL. J Cataract Refract Surg. Dec 2011; 37(12):2214-2217. PMID 22108117
  18. National Institute for Health and Clinical Excellence (NICE). Photochemical Corneal Collagen Cross-Linkage Using Riboflavin and Ultraviolet A for Keratoconus and Keratectasia, IPG466. 2013; Accessed May, 2015.
  19. National Keratoconus Foundation. Crosslinking. Available online at: Last accessed May, 2015.
  20. Blue Cross and Blue Shield Association. Corneal Collagen Cross-Linking. Medical Policy Reference Manual, Policy 9.03.28, 2015.







Unlisted procedure, anterior segment of eye







New policy, add to Vision section. New policy created with literature review through January 2012; clinical input reviewed; considered investigational.


Update Coding Section – ICD-10 codes are now effective 10/01/2014.


Update Related Policies. Delete 9.03.05 as it was archived.


Replace policy. Policy updated with literature review through January 29, 2013; references 5, 6, 11 added and references reordered; policy statement unchanged. Remove Related Policy 9.03.14 as it was archived.


Annual Review. Policy updated with literature review through February 7, 2014; reference 4 added; policy statement unchanged. CPT 66999 added to coding section; it previously appeared only within the Policy Guidelines section.


Annual Review. Policy updated with literature review through February 25, 2015. References 3, 4, 11 added; others renumbered. Policy statement unchanged.

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