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Corneal Collagen Cross-Linking

Policy Number: MP-639

Latest Review Date: April 2019

Category: Medical                                                              

Policy Grade:  A

Description of Procedure or Service:

Corneal collagen cross-linking (CXL) is a photochemical procedure approved by the Food and Drug Administration 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.

Keratoconus and Ectasia

Keratoconus is a bilateral dystrophy 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. Results from a longitudinal study with 7 years of follow-up showed that, over the study period, there was a decrease of 2 high- and 4 low-contrast letters in best-corrected visual acuity (BCVA). About 1 in 5 patients showed a decrease of 10 or more letters in high-contrast visual acuity and one-third of patients showed a decrease of 10 or more letters in low-contrast visual acuity. Over 8 years of follow-up, there was a mean increase of 1.44 diopters (D) in First Definite Apical Clearance Lens (a rigid contact lens to measure corneal curvature) and 1.6 D in flatter keratometric reading.

Ectasia (also known as keratectasia, iatrogenic keratoconus, or secondary keratoconus) is a serious long-term complication of laser in situ keratomileusis (LASIK) surgery and photorefractive keratectomy. It is similar to keratoconus, but occurs postoperatively and primarily affects older populations. It may result from unrecognized preoperative keratoconus or, less frequently, from the surgery itself. Similar to keratoconus, it is characterized by progressive thinning and steepening of the cornea, resulting in corneal optical irregularities and loss of visual acuity.

Treatment

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 (See MP 080 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, a 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 (CXL) has the potential to slow the progression of disease. It is performed with the photosensitizer riboflavin (vitamin B₂) and ultraviolet A (UVA) irradiation. There are 2 protocols for CXL.

  1.  Epithelium-off CXL (also known as “epi-off”): In this method, about 8 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 1-3 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 CXL (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 CXL treatment approved by the Food and Drug Administration (FDA) is the epithelium-off method. There are no FDA-approved CXL treatments using the epithelium-on method. CXL is being evaluated primarily for corneal stabilization in patients with progressive corneal thinning, such as keratoconus and corneal ectasia following refractive surgery. CXL may also have anti-edematous and antimicrobial properties.

Policy:

Effective for dates of service on or after April 26, 2017:

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 1 or more of the following:

  • An increase of 1 D in the steepest keratometry value
  • An increase of 1 D in regular astigmatism evaluated by subjective manifest refraction
  • A myopic shift (decrease in the spherical equivalent) of 0.50 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 not medically necessary and 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.

Effective for dates of service prior to April 26, 2017:

Corneal collagen cross-linking is not medically necessary and is considered investigational for all indications.

Key Points:

The most recent literature update was performed through January 9, 2019.

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function- including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Corneal Collagen Cross-Linking for Keratoconus and Ectasia

The evidence base for Food and Drug Administration (FDA) approval of epi-off corneal collagen cross-linking (CXL) for the treatment of progressive keratoconus and corneal ectasia after refractive surgery consists of 3 randomized, parallel-group, open-label, sham-controlled trials that are summarized below.

In addition, there are systematic reviews, 2 RCTs, multiple prospective controlled studies, and uncontrolled trials reporting on longer term outcomes of the procedure. These RCTs are summarized in a section below.

Pivotal Trials

The 3 open-label RCTs are summarized in Table 1. The primary end point was a 1-diopter (D) reduction in the maximum corneal curvature (Kmax) at month 3. Because corneal stromal remodeling associated with healing response after CXL requires 6 to 12 months to stabilize, the time point for primary end point was changed from 3 to 12 months. This end point was better suited for evaluating the long-term clinical benefits of the CXL treatment. In all 3 trials, only 1 eye per patient was designated as the experimental eye. Patients with corneal ectasia diagnosed after laser in situ keratomileusis (LASIK) or photorefractive keratectomy or those with progressive keratoconus were included in these trials. Progressive keratoconus was defined as one or more of the following over a period of 24 months or less before randomization:

  • An increase of 1 D in the steepest keratometry value
  • An increase of 1 D in regular astigmatism evaluated by subjective manifest refraction
  • A myopic shift (decrease in the spherical equivalent) of 0.50 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.

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 débridement or have the ultraviolet A (UVA) light source turned on. For sham subjects who received CXL treatment at month 3 or month 6, the last Kmax measurement recorded prior to CXL treatment was carried forward in the analysis for later time points. This is a conservative method of analysis in this situation, because it reduces the expected worsening over time in untreated patients. Almost all patients in the sham group received CXL treatment at month 3 or 6 and therefore the analysis compared the Kmax at month 12 in the CXL group with the Kmax at month 3 or 6 in the sham group. In each study, Kmax was assessed at baseline and at months 1, 3, and 12.

Table 1. Summary of Pivotal Trial Characteristics and Results

Study

Study

Design

Dates

Patients (N or n)

Difference in Mean Change in Kmax From Baseline to 12 Months (95% CI)ᵇ

Unpublished

UVX-001

RCT

2008-2010

Keratoconus (58)

Ectasia (49)

1.9 D (-3.4 to0.3)

  -2.0 D (-3.0 to -1.1)

Hersh et al (2011)ª

UVX-002

RCT

2008-2010

Keratoconusonly(147)

  -2.3 D (-3.5 to -1.0)

Hersh et al (2011)ªᵇ

UVX-003

RCT

2008-2011

Ectasia only (130)

  -1.1 D (-1.9 to -0.3)

CI: confidence interval; D: diopter; Kmax: maximum corneal curvature; RCT: randomized controlled trial.

a Hersh et al (2011)e6 reported early trial results that included data from 49 of 147 patients in the UVX-002 trial and 22 of 130 patients in the UVX-003 trial. These results are not discussed.

b In UVX-003, 4 patients in the collagen cross-linking group had missing baseline Kmax values and were excluded from the analysis.

Maximum Corneal Curvature (Kmax)

The CXL-treated eyes showed increasing improvement in Kmax from months 3 through 12 (data not shown). The difference of the change in Kmax from baseline to month 12 between CXL-treated eyes and sham-treated eyes is summarized in Table 1 and was statistically significant from 6 month onward in favor of CXL treatment.

Best Spectacle-Corrected Visual Acuity

The visual acuity outcomes as assessed by mean improvement in best spectacle-corrected visual acuity (BSCVA) and responder analysis (gain of ≥15 letters on Early Treatment Diabetic Retinopathy Study [ETDRS] is considered clinically meaningful) are summarized in Tables 2 and 3, respectively. Statistical procedures to control for Type I error for multiple comparisons were not described in either the sponsor or in FDA documents. Therefore, these results should not be used for statistical inference. The results summarized in Tables 2 and 3 are based on last observation carried forward (LOCF) analysis. In the pooled analysis of the observed data, the mean change in sham-control patients for progressive keratoconus at 6 months was +1.1 letter (n=38) compared with +5.8 (n=96) for CXL-treated patients, yielding a difference of 4.7 letters in favor of CXL treatment. Respective numbers for patients with ectasia were -0.4 letters (n=88) vs +4 letters (n=91), yielding a difference of 4.4 letters in favor of CXL treatment. Notably, FDA-approved labels for Photrexa and Photrexa Viscous do not include any visual acuity outcomes.

Table 2. Summary of BSCVA Outcomes in the Pivotal Trials

Study

Patients(n or N)

Mean Change in BSCVA from Baseline to 12 Months

Differenceª

CXL-Treated Eyes

Sham-Controlled Eyes

UVX-001

Keratoconus (58)

Ectasia (49)

+ 7.2

+5.0

+3.4

-0.9

+3.8 letters

+5.9 letters

UVX-002

Keratoconus only (147)

       +5.0

     +1.4

      +3.6 letters

UVX-003

Ectasia only (130)

       +5.0

    -0.1

       +5.1 letters

Pooled

Keratoconus (205)

Ectasia (179)

 +5.6

 +5.0

 +2.0

 -0.3

   +3.6 letters

   +5.3 letters

Adapted from Avedro (2015).7 BSCVA: best spectacle-corrected visual acuity; CXL: corneal collagen cross-linking.

a Results should be considered exploratory.

Table 3. Summary of ETDRS Chart Outcomes in the Pivotal Trials

Study

Patients(n or N)

Difference from Baseline to 12 months in % Patients who gained ≥15 letters on ETDRS

Differenceª

CXL-Treated Eyes

Sham-Controlled Eyes

UVX-001

Keratoconus (58)

Ectasia (49)

+ 24.1%

+21.7%

+21.4%

+4,2%

+2.7%

+17.5%

UVX-002

Keratoconus only (147)

+17.4%

+2.8%

+14.6%

UVX-003

Ectasia only (130)

+9.2%

+4.8%

+4.4%

Pooled

Keratoconus (58)

Ectasia (49)

19.4%

12.5%

8.1%

4.7%

+11.3%

+7.8%

Adapted from Avedro (2015). CXL: corneal collagen cross-linking; ETDRS: Early Treatment Diabetic Retinopathy Study.

a Results should be considered exploratory.

Other Randomized Controlled Trials

Keratoconus

Hersh et al (2017) analyzed 205 patients who had keratoconus treated with CXL (n=102) or a sham procedure (n=103) in a Phase 3, prospective, randomized, controlled trial. At 1 year, those in the treatment group had a significant decrease in Kmax score (1.6) compared with baseline, while the control group saw an increase in Kmax (1.0); the between-group difference in Kmax change was 2.6 D (p<0.001). Mean corrected distance visual acuity (CDVA) improved significantly more in the treatment group (5.7 logMAR) than in the control group (2.2 log MAR; between-group difference, 3.5 logMAR; p<0.01). A similar finding, though statistically insignificant, was observed for mean uncorrected distance visual acuity (UDVA), with the treatment group improving by 4.4 logMAR, compared with the control group (2.6 logMAR; between-group difference, 1.8 logMAR). Endothelial cell count did not change significantly from baseline to 1 year in either group. The trial was limited in that patients in the control group were allowed to switch to CXL treatment after 3 months; thus, their data were imputed based on the LOCF method. Also, in the control group, patients did not undergo removal of their epithelium.

Renesto et al (2010) reported on 2-year results of a randomized trial that compared CXL with 1 month of riboflavin eye drops in 39 eyes of 31 patients with keratoconus. After 3 months, all patients received intrastromal corneal ring segments (See MP 080 Implantation of Intrastromal Corneal Ring Segments). 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 intrastromal corneal ring segments insertion. There were no significant differences between the 2 groups for UCVA, BCVA, or in 3 topographic parameters (flattest K, steepest K, and average keratometry) throughout the 24-month follow-up.

Systematic Reviews

Keratoconus

A Cochrane review (2015) evaluated the use of corneal CXL for the treatment of keratoconus. The literature search was conducted in August 2014 and did not include all of the Phase 3 trials submitted to FDA (described previously). Reviewers included 3 small RCTs conducted in Australia, the United Kingdom, and the United States, which enrolled a total of 225 eyes and analyzed 219 eyes. All 3 trials were at high risk for performance bias (lack of masking), detection bias (only 1 trial attempted to mask outcome assessment), and attrition bias (incomplete follow-up). Reviewers did not conduct a meta-analysis due to differences in measuring and reporting outcomes. The overall quality of the evidence was judged to be very low, primarily due to downgrading the evidence due to the risk of bias in the included studies, imprecision, indirectness, and publication bias.

In 2016, Meri et al reported results of a systematic review and meta-analysis of ocular functional and structural outcomes in patients with keratoconus who underwent CXL treatment. Reviewers reported a modest but statistically nonsignificant improvement in visual acuity of 1 to 2 Snellen lines at 3 months or more after undergoing CXL. Reviewers concluded that, although CXL appeared to be effective at halting the deterioration of keratoconus, it was only slightly effective at improving visual acuity.

McAnena et al (2017) reported results of a systematic review and a meta-analysis assessing the efficacy of CXL treatment for keratoconus in pediatric patients. A total of 13 articles, published between May 2011 and December 2014, examining 490 eyes of 401 patients (mean age, 15.25 years), were included in the meta-analysis. Bias assessment of individual studies was not included. Reviewers reported a significant improvement in BCVA at 6 months (standardized mean difference [SMD], -0.66; 95% confidence interval [CI], -1.22 to -0.11; p=0.02), which was maintained at 1 year (SMD = -0.69; 95% CI, -1.15 to -0.22; p<0.01). Two-year data were available for 3 studies (n=131 eyes) and the improvement in BCVA remained significant (SMD= -1.03; 95% CI, -2 to -0.06; p=0.04).

Uncontrolled Studies

Keratoconus

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

In 2008, Raiskup-Wolf et al reported outcomes of 241 eyes (272 patients) treated with CXL, with a minimum of 6 months of follow-up. 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 (Kmax) 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), Kmax improved by a mean of 2.57 D in 67% of eyes while BCVA improved by at least 1 line in 58% of eyes.

A 2010 publication from the Siena Eye Cross Study reported 52-month mean follow-up (range, 48-60 months) for 44 keratoconic eyes treated with CXL. Follow-up evaluations were performed at 1, 2, 3, 6, 12, 24, 36, 48, and 60 months after CXL. Topographic analysis showed the following mean K reading reductions: -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.

The French National Reference Center for Keratoconus published their findings in 2011. 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 Kmax had decreased by more than 2 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 2 or more Snellen lines of visual acuity. This retrospective study had a low proportion of patients available at the 12-month follow-up.

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

In 2015, Raiskup-Wolf et al  published 10-year follow-up of CXL treatment in 34 eyes (24 patients) with progressive keratoconus. Mean patient age at the time of treatment was 28 years (range, 14-42 years). 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 after 5 years and one after 10 years, without adverse sequelae. One of the 34 eyes treated developed a permanent corneal scar. These studies are limited by their retrospective designs and the small number of cases with extended follow-up.

In 2016, Padmanabhan et al retrospectively analyzed 377 eyes of 336 patients (mean age, 15 years) who underwent CXL for progressive keratoconus. There was significant improvement in mean BSCVA from 0.33 to 0.27 logMAR (p<0.05). The authors found that the benefits of CXL in stabilizing keratoconus were maintained for more than 2 years in most pediatric eyes.

Padmanabhan et al (2017) also published follow-up results from the retrospective study previously mentioned of 377 eyes in 336 pediatric patients. Of 59 eyes for which investigators had longer term follow-up data (4 to 6.7 years), 30.9% showed worsening CDVA, and 24% showed corneal steepening of greater than 1 D (Kmax). These results showed the majority of patients still experienced improvements or stabilization of keratoconus-related outcomes after CXL, but suggested that, long term, there may be less efficacy.

Toprak et al (2017) retrospectively analyzed 29 eyes from pediatric patients (age range, 10-17 years) whose progressive keratoconus was treated with unilateral CXL treatment. From baseline to 2-year follow-up, there was a significant decrease in mean CDVA (0.34 logMAR to 0.13 logMAR; p<0.001). Maximum keratometry (Kmax) measures decreased from baseline 54.65 to 53.25 at 2 years (p=0.034), while anterior chamber parameters, corneal thickness, and corneal volume were not significantly affected by CXL after 2 years (p>0.05). Several parameters of the Scheimpflug imaging system were improved following CXL treatment: index of surface variance (ISV) decreased from 69.75 at baseline to 62.95 at 2 years (p=0.004); keratoconus index (KI) decreased from 1.16 (p=0.001); center keratoconus index (CKI) decreased from 1.05 to 1.04 (p=0.004); and index of height decentration (IHD) decreased from 0.056 to 0.042 (p=0.001). Radius of minimum curvature (Rmin) increased significantly from baseline to 2 years (6.21 to 6.36; p=0.007), although 2 other indices (indices of height and vertical asymmetry) did not change significantly. The authors noted that follow-up beyond 2 years is required to make long-term assessments of CXL as treatment for keratoconus, but concluded that their results seemed favorable for postoperative outcomes.

Badawi et al (2017) published a prospective nonrandomized observational study of accelerated CXL to treat pediatric patients with keratoconus. Of the 25 patients (33 eyes) enrolled, 80% were male, and most patients (n=17) received unilateral CXL, administered with Vibex Rapid solution and Vega CBM X-Linker. The group’s mean unaided and aided visual acuity were significantly improved at all time points (3, 6, and 12 months): at 12-month follow-up, the mean unaided visual acuity score was 0.34, which was a significant decrease compared with preoperative mean score (0.54; p<0.001). For aided visual acuity, there was a similar decrease from preoperative (0.36) to 12-month (0.17 time points (p<0.001). Mean corneal astigmatism values also decreased significantly (preoperative 2.4 D decreased to 2.01 D at 12 months; p<0.001). The mean Kmax showed an average flattening of 1.2 D in 1 year (49.12 D decreasing to 47.9 D; p<0.001); the authors reported significant improvements in other measures such as central pachymetry, maximum anterior elevation, average progression indices, and Q values. A limitation of the study was the slight increase observed in posterior surface elevation, which, contrary to other study measures, showed no significant positive effect 12 months after accelerated CXL (p=0.9). Advising further study of the procedure, the authors noted that the unusual result might be accounted for by the choice of Pentacam as a corneal analysis tool, because there might have been corneal artifacts present during evaluation.

Knutsson et al (2018) published a prospective cohort study of 43 patients (52 eyes) between the ages of 12 and 17 who underwent CXL as treatment for keratoconus in 1 or both eyes. Two-year outcomes were reported for all patients, although longer-term (up to 7 years) follow-up was available for 21 eyes. At 2 years, overall mean Kmax decreased from 59.30 ± 7.08 to 57.07 ± 6.46 (p<0.001), and overall mean UCVA and BSCVA decreased, although not significantly. Additional analyses were conducted of patients whose eyes had Kmax values of 60 D or greater (n=25), compared with those whose keratometry was less severe (<60 D). As with the overall findings, mean Kmax for both cohorts was significantly decreased for both cohorts, while neither UCVA nor BSCVA measures changed significantly at 1 or 2 years. In patients with advanced keratoconus, mean Kmax decreased from 64.94 (95% CI, 62.94 to 66.94) to 62.25 (95% CI, 60.55 to 63.95) at 2 years (p<0.001); for the less-advanced cohort, mean Kmax decreased from 53.88 (95% CI, 52.48 to 55.28) at baseline to 52.08 (95% CI, 50.68 to 53.48) at 2 years (p<0.001). While most findings were favorable for the efficacy of CXL in treating even severe keratometry, the authors noted that the study was limited by the use of 2 pachymetric measurement techniques (optical coherence tomography and ultrasound) rather than a single technique across the study. Further, the lack of full long-term data for all patients limited the study to reporting only 2-year outcomes.

Adverse Events

The safety analysis conducted by FDA included 512 eyes (293 keratoconus, 219 corneal ectasia) in 364 patients who received CXL treatment. As described earlier, the procedure involves removing the corneal epithelium to enhance the riboflavin solution’s penetration. As a result, patients may develop a range of ocular adverse reactions, including corneal opacity (haze), corneal epithelial defects, punctate keratitis, corneal striae, eye pain, reduced visual acuity, blurred vision, dry eye, and photophobia among others. Most adverse reactions resolved in the first month, while others took up to 12 months to resolve. However, in 1% to 6% of patients, these adverse reactions could continue beyond 12 months.

Summary of Evidence

For individuals who have progressive keratoconus who receive CXL using riboflavin and ultraviolet A, the evidence includes multiple RCTs, systematic reviews, and nonrandomized studies. Relevant outcomes are change in disease status, functional outcomes, and treatment-related morbidity. In both pivotal RCTs, the primary end point (an intermediate outcome) of reducing maximum corneal curvature (Kmax) by 1 D was achieved at month 3 and maintained at months 6 and 12 in CXL-treated patients compared with sham controls. In both RCTs, the difference in mean change in Kmax from baseline to 12 months was 1.9 D and 2.3 D, respectively, favoring the CXL-treated patients. Long-term follow-up for visual acuity outcomes are needed. The adverse events associated with CXL 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 6 to 12 months. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Practice Guidelines and Position Statements

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 (CXL) using riboflavin and ultraviolet A updated and replaced its 2009 guidance. The 2013 guidance stratified NICE 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.”

U.S. Preventative Services Task Force Recommendations

Not applicable.

Key Words:

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

Approved by Governing Bodies:

In 2016, riboflavin 5’-phosphate in 20% dextran ophthalmic solution (Photrexa Viscous®; Avedro) and riboflavin 5’-phosphate ophthalmic solution (Photrexa®; Avedro) were approved by the U.S. Food and Drug Administration for use with KXL System in corneal collagen cross-linking for the treatment of progressive keratoconus and corneal ectasia after refractive surgery.

Benefit Application:

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.

Current Coding:

CPT Codes:

0402T

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

HCPC Codes

J2787

Riboflavin 5'-phosphate, ophthalmic solution, up to 3 mL (Effective 01/01/2019)

References:

  1. 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.

  2. Avedro Inc. Avedro Briefing Package for Joint Meeting of the Dermatologic and Ophthalmic Drugs Advisory Committee and Ophthalmic Device Panel of the Medical Devices Advisory Committee NDA 203324: Photrexa Viscous and Photrexa (riboflavin ophthalmic solution) and KXL System (UVA light source) Avedro, Inc. 2015; Accessed February 7, 2017

  3. Avedro Inc. Photorexa® Viscous and Photorexa® Prescribing Label. //www.accessdata.fda.gov/drugsatfda_docs/label/2016/203324s000lbl.pdf. Accessed February 23, 2018.

  4. Badawi AE. Accelerated corneal collagen cross-linking in pediatric keratoconus: One year study. Saudi J Ophthalmol. Jan-Mar 2017; 31(1):11-18.

  5. 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

  6. 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.

  7. Center for Drug Evaluation and Research: FDA. Summary Review: Application Number 203324Orig2s000. //www.accessdata.fda.gov/drugsatfda_docs/nda/2016/203324Orig2s000SumR.pdf. Accessed February 23, 2018.

  8. 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.

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  10. 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.

  11. 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

  12. 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.

  13. Inc A. Avedro Briefing Package for Joint Meeting of the Dermatologic and Ophthalmic Drugs Advisory Committee and Ophthalmic Device Panel of the Medical Devices Advisory Committee NDA 203324: Photrexa Viscous and Photrexa (riboflavin ophthalmic solution) and KXL System (UVA light source) Avedro, Inc. 2015; //www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DermatologicandOphthalmicDrugsAdvisoryCommittee/UCM435022.pdf. Accessed February 7, 2017.

  14. 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.

  15. McAnena L, Doyle F, O'Keefe M. Cross-linking in children with keratoconus: a systematic review and meta-analysis. Acta Ophthalmol. Sep 28 2016.

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  17. Meiri Z, Keren S, Rosenblatt A, et al. Efficacy of corneal collagen cross-linking for the treatment of keratoconus: a systematic review and meta-analysis. Cornea. Mar 2016; 35(3):417-428.

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  19. 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.

  20. 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.

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  23. 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.

  24. Sykakis E, Karim R, Evans JR, et al. Corneal collagen cross-linking for treating keratoconus. Cochrane Database Syst Rev. 2015; 3:CD010621.

  25. 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.

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Policy History:

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.

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.