Clinician Insights

Poll: Ophthalmologists Eager to Use Newly Approved Corneal Crosslinking

John Watson

June 13, 2016

With the recent approval of first-in-class corneal collagen crosslinking (CCL) for progressive keratoconus, the US Food and Drug Administration (FDA) is giving American ophthalmologists access to a treatment that their counterparts in Canada, Europe, and elsewhere in the world have used for roughly a decade.

According to the results of a recent Medscape Medical News poll, there is considerable enthusiasm to take advantage of this opportunity. Of the 252 ophthalmologist physicians polled at the time of publication, 3 out of 4 said they were likely to begin using CCL in their practice.


Table 1. Eager Adopters: How Likely Are You to Incorporate Corneal Crosslinking Into Your Practice?*

Very likely 58%
Likely 19%
Neutral/not certain 8%
Not likely 6%
Not at all likely 6%

*As of 5 pm EST, May 18.


New Tool for Avoiding Corneal Transplantation

The FDA's decision, announced in mid April, extends to three different components used in CCL: a riboflavin ophthalmic solution (Photrexa, Avedro, Inc) and a version containing dextra (Photrexa Viscous), as well as the electronic device (KXL System) used to irradiate these solutions after corneal application.

In the approved technique for performing CCL, the cornea is de-epithelialized (also known as epithelia-off) and saturated with the riboflavin solution for 30 minutes. The cornea is then exposed for 30 minutes to ultraviolet A light applied via the electronic device. This stimulates an interaction with the collagen fibers that results in stiffening.

Keratoconus, the most common cornea ectatic disorder, typically arises in the second decade of life and early adulthood. Patients experience a gradual thinning of the central cornea that produces a cone-shaped bulge, which eventually leads to myopia, irregular astigmatism, and visual impairment.

"Previous treatments for patients with keratoconus have been unchanged for the lifetime of most ophthalmologists," explained Roger Steinert, MD, chair of the Department of Ophthalmology and director of the Gavin Herbert Eye Institute at the University of California, Irvine.

In the early stages of keratoconus, patients can make due with eyeglasses, although more moderate cases require contact lenses, including rigid gas-permeable lenses. In the approximately 20% of patients whose keratoconus progresses to more advanced stages, it may be necessary to perform corneal transplant. For American ophthalmologists, CCL therefore represents a new option for intervening before transplant, and one with a proven ability to enhance visual acuity while halting, and sometimes even moderately reversing, keratoconus progression.

A Welcome Import

CCL may be new to US markets, but it is far from an unknown commodity. This likely contributes to the high level of awareness reflected in these poll numbers.

"CCL has been available through much of the world for over a decade," said Dr Steinert. "The average ophthalmologist has been very aware of the treatment for 5 to 10 years."

In Medscape's poll, 95% of respondents said they thought CCL would reduce the need for corneal transplant in their keratoconus patients. The desire to have at-risk patients avoid such a fate, coupled with the frustrating fact that CCL was relatively easily available to anyone with a passport, had in earlier years led several ophthalmologists to find creative solutions.

"Some people in the US have gone outside the regulatory rules and bought CCL machines from countries around the world," said Christopher J. Rapuano, MD, professor of ophthalmology at the Sidney Kimmel Medical College of Thomas Jefferson University and chief of cornea services at the Wills Eye Hospital in Philadelphia, Pennsylvania. "They've had to smuggle them in or go through customs under these unusual circumstances, such as saying they were only using their machine on animals. Others weren't comfortable doing that but felt they weren't providing state-of-the-art care for their patients."

Corneal Specialists Most Likely to Benefit

Although 77% of poll respondents said they would incorporate CCL, both Dr Rapuano and Dr Steinert believed that it was unlikely that that many physicians would do so, because to apply the treatment requires specific equipment and perhaps a specialist's background.

"Results are likely skewed by either the lack of understanding of this procedure or a misunderstanding of the commitment that an ophthalmologist must take,” Dr Steinert said. "Certainly the corneal subspecialists ― and quite possibly 77% as indicated ― will be eager to use it in their practice."

It is estimated that keratoconus affects 1 in every 2000 Americans. In the Medscape reader poll, the majority of ophthalmologist physicians (72%) said they see from 1 to 10 patients with this condition every month; 16% see more. Poll numbers also suggest that the overall eagerness to apply CCL extends to indications beyond keratoconus.

Table 2. Other Applications: Besides Keratoconus, Which Other Conditions Do You Think Corneal Crosslinking Would Be Most Useful For?*

Corneal ectasia after refractive surgery such as LASIK 67%
Infectious keratitis 17%
Corneal ulcers 6%
Refractive correction 3%
Other 4%

*As of 5 pm EST, May 18.


"Almost all of the interest is also connected to the issue of corneal ectasia after refractive surgery," said Dr Steinert. "All the data are very favorable to doing corneal crosslinking for that indication. Fortunately, the number of cases of crosslinking for ectasia will be significantly less due to the better understanding of the source of ectasia and its avoidance."

Refining CCL in the Near Future

The FDA's approval was based on data from three prospective, randomized, 12-month trials in which patients underwent 30-minute crosslinking or sham treatment in one eye. During a period of 3 to 12 months, patients in the crosslinking arm experienced decreases from baseline in maximum corneal curvature of between -1.9 and -2.3 diopters.

Dr Rapuano participated in separate trials of CCL that did not directly lead to the FDA approval. In these trials, patients received exposures of shorter duration to the ultraviolet light, lasting 2, 4, and 8 minutes. He said that overall, his experience with the treatment was very positive.

"Our patients found it uncomfortable to painful for the first few days, but the vast majority felt better within 4 to 5 days," he said. "They experience a little bit of haze over the first few months, which tends to disappear."

He said that he is interested in seeing data on the various permutations of CCL, such as use of exposures with higher-power ultraviolet light over shorter periods ― a technique employed in his own studies. If proven equally beneficial, this approach would reduce the burden of administration. He is also interested in finding out whether so-called epithelium-on versions of CCL prove equally effective.

"The vast majority of the postoperative complications, such as pain, infection, and scarring, are caused by the big scratch required in the epithelium-off technique," Dr Rapuano said. "There are people globally and in the US using different machines and different riboflavin solutions with an epithelium-on technique, many of whom feel that their particular technique is as good as the epithelium-off technique."

Although the published data regarding use of the epithelium-on technique are not robust, if proven successful, it could lead to more procedures in which patients undergo CCL in both eyes. In currently approved variations, most patients undergo treatment in one eye at a time to allow for proper recovery and unimpaired function.

As physicians await answers to these questions, Dr Rapuano said they should be excited about this newly approved treatment for progressive keratoconus. However, he cautioned that they should also be clear with their patients about the goals and expected outcomes of CCL.

"If patients think that they're doing this treatment to get better vision or decrease their keratoconus, while that does happen maybe 10% to 20% of the time, that's not the goal of treatment. Patients and doctors have to understand that the goal is stability and not getting worse."


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