AVASTIN UPDATE ll: AAO supports Medicare coverage for off-label Avastin use

April 24, 2006, As reported by the OSN Supersite:

AAO supports Medicare coverage for off-label Avastin use

SAN FRANCISCO — A drug being used off-label for the treatment of age-related macular degeneration should be considered for Medicare coverage, said the American Academy of Ophthalmology. According to an AAO press release, the organization sent a letter to U.S. regulators supporting Medicare reimbursement for the drug.

AAO said in its letter to the Centers for Medicare and Medicaid Services that it “supports reimbursement for treating AMD with intravitreal injections of bevacizumab, to meet the medical needs of many patients who have not responded to therapy with ocular photodynamic therapy with verteporfin or intravitreal pegaptanib.”

Avastin (bevacizumab, Genentech) is approved in the United States for the systemic treatment of colorectal cancer. The intravitreal dosage is being used by “a large number” of retinal specialists who believe it is “reasonable and medically necessary for treatment of some patients with neovascular AMD,” AAO said.

“The scientific studies related to the use of intravitreal injections of bevacizumab for the treatment of neovascular AMD are supportive,” AAO said in the letter, “but they are not conclusive of its safety and efficacy.”

H. Dunbar Hoskins, MD, said the letter is not to be interpreted as an endorsement by the AAO of the off-label use, but that physicians who choose to use intravitreal Avastin “be reimbursed as they are with other off-label therapies.”

The AAO said it supports physician reimbursement, but limits the support to “patients who are deemed by their treating physician to have failed Food and Drug Administration-approved therapies” or for whom the physician believes would benefit from the use of the intravitreal version.

“The Academy is concerned that in spite of the current treatments available, fewer than 10% of patients have had significant improvement in visual acuity,” Dr. Hoskins, AAO executive vice president, said in the release. “Most patients continue to lose vision after 1 year of therapy.”

According to the release, AAO issued its letter in response to member requests for clarification on the coverage issue. Further, the AAO said more than 6,800 injections in 5,055 patients from 68 centers in 12 countries have been documented with a low rate of ocular or systemic adverse events.

The American Society of Retinal Specialists survey found 4% of 289 respondents had noted any thromboembolic complications thought to be related to the intravitreal treatment, and 92% of respondents said they believed intravitreal bevacizumab was “somewhat better” or “much better” than other approved or covered therapies, the release said.

Author’s Note on Avastin

Since the original posting on January 31st, I have now added four updates on this important drug for treating age-related macular degeneration. In addition to the posting you are reading, here is a listing (with links) to the others:

Avastin: A New Hope for Treating AMD

Avastin Update: Medicare not Likely to Cover its Use

ARVO 2006: A Further Update on Both Avastin and Lucentis for Treating AMD

Avastin/Lucentis Update 4: FDA Approves Lucentis for Treating Wet AMD

Menu – Part 5: A Further List of Potential Publications

First, three updates:

Avistin Update II: AAO supports Medicare Coverage for Off-label Avistan Use

As reported by the OSN Supersite, the Academy of Ophthalmology plans to support the push to have Medicare pay for the off-label use of Avastin in treating AMD.

Custom Ablation #9: Questions.....and Answers

Along with its April 2006 issue, CRS Today published a supplement (sponsored by an unrestricted grant from Advanced Medical Optics) that answers the questions I had raised in previous columns on customized ablation concerning whether wavefront-optimized LASIK was as good as wavefront-guided ablation. (And, were either better than conventional LASIK?)

ARVO 2006: A Further Update on Both Avastin and Lucentis for Treating AMD

Michael Lachman of Lachman Consulting LLC released his latest EyeQ Report, covering developments on both Lucentis and Avastin from the 2006 ARVO meeting held in Sarasota, FL. The report contains the two-year results on the Lucentis MARINA Study and the latest data on the use of intravitreal Avastin.

Next, I intend to post three columns, written in the summer of 1994, that take an inside look into the patent situation in both refractive surgery and in the medical/surgical specialties. I call the series, Entering the Patent Zone.

Entering the Patent Zone: The Volatile History of Medical Laser Patents

In this initial look at the history of medical laser patents, I will introduce you to Gordon Gould and Patlex; Ken Fox and Pillco; and Summit Technology and VISX and Pillar Point Partners, as well as Dr. Rangananth Srinivasan of IBM. In doing so, you will be exposed to some of battles being fought, and those yet to be resolved.

Entering the Patent Zone, Part 2: A Sampling of the Medical Laser Patents Issued in 1993/1994

1993 and 1994 represented a prolific time in the issuance of patents for several of the major medical laser companies. I reviewed a sampling of some of the more interesting medical laser-related patents issued in 1993 and the first several months of 1994.

And finally,

Entering the Patent Zone, Part 3: Optical Feedback Patents Discovered

While undertaking a consulting assignment, I learned about an obscure company that was supposedly developing a unique diagnostic system. In hunting this lead down, I came across a very interesting story and patents. This is the story of Dr. Paul Lovoi and Silicon Surgical.

Customized Ablation #8: An AAO 2002 Update: Classic vs. Custom LASIK -- The Battle Continues

This is the 8th and final article in the series of eight articles chronicling the development of Customized Ablation or Wavefront Directed Lasik. This column was written following the2002 AAO meeting, and was published in the January1, 2003 issue of Ocular Surgery News (but was not put online).

Technology Update

An AAO 2002 Update: Classic vs. Custom LASIK -- The Battle Continues

Irving J. Arons
Managing Director
Spectrum Consulting

With the first customized ablation protocol approved by the FDA -- Alcon's LADARVision system with LADARWave diagnostics -- and several other companies six-month results reported and filed, the battle continues whether the market will turn to custom ablation over classic LASIK. As was pointed out during the "Catch the Wave" combined session of the ISRS and RSIG, the push toward custom ablation has raised the outcomes levels of standard or classic LASIK. With improved laser algorithms, use of eye trackers, improved microkeratomes, and better diagnostics for screening patients, classic LASIK results, especially wavefront-assisted LASIK (wherein the wavefront device is used for screening and planning the ablation) have risen to very high levels of uncorrected acuity and patient satisfaction. This, again, raises the question of the need for customized ablation.

The results obtained with customized ablation, regardless of the laser platform used are believed to be, in general, about 10% to 15% better than the results obtained with classic LASIK. However, because customized ablation treats higher orders of aberrations (coma, tilt and spherical aberrations), in addition to the lower orders of sphere, cylinder, and defocus, the quality of vision (contrast sensitivity and night vision) is dramatically improved. It is our believe (as well as of several other analysts) that custom ablation will aid in improving patient perceptions of the results that they might obtain and will serve as a catalyst toward driving procedure growth over the next several years. In fact, it could provide for a 13% to 15% growth in procedures in 2003, bringing the market back to the levels seen in 2000 before the recent slide in procedures occurred. This, of course, is dependent on a return of economic growth and consumer confidence.

From all appearances, the already approved classic LASIK laser systems -- the VISX Star S3, Alcon LADARVision, Bausch & Lomb Tecnolas 217z, and the Nidek EC5000 -- all appear to provide similar results. The limiting factor is now the wavefront diagnostics. Even though these systems have improved vastly over the last two years, there is no standardization and results on various systems on the same eyes are different. In a study reported by Erin Durrie Stahl during the ISRS pre-meeting, a set of 20 eyes were tested on six different wavefront and ray tracing diagnostics. Although the results were repeatable on each system, they were not comparable across systems. Standardization is truly needed.

In fact, not all systems can capture all eyes. In his presentations, Prof. Theo Seilor admitted that the Tscherning aberrometer (used with the WaveLight Allegretto and Schwind ESIRIS), did not capture 15%-20% of the eyes tested. And, similar results are reported with other systems, especially with abnormal eyes. More development and standardization is needed before wavefront diagnostics become the standard of care. Another open question is whether topography, to capture the curvature of the cornea, should be added to wavefront systems in order to obtain a complete picture of the aberrations of the eye. This is currently done by Bausch & Lomb, Nidek, and LaserSight (but the latter without the wavefront diagnostic as yet) -- and Carl Zeiss Meditec, Schwind, and WaveLight internationally.

And, Jack Holliday has been exonerated! After preaching for several years, the congregation has finally heard the message -- prolate corneas are indeed better than oblate (eagle eyes vs frogs!). Several laser manufacturers now incorporate algorithms that produce prolate shaped corneas (Carl Zeiss Meditec, WaveLight, and Schwind, for example) and are getting much improved outcomes.

As reported by Marguerite McDonald, MD, and others, the key to obtaining good customized ablations is going to be "registration, capture, match, and treat". The diagnostic device needs to be capable of registering the position of the eye, capture the abnormalities, match the eye registration in front of the laser, and be able to treat the abnormalities -- hopefully without inducing further aberrations.

The latter raises another question. Since the use of the microkeratome and customized ablation algorithms seem to induce some degree of higher order aberrations, will the use of "Advanced Surface Ablation" (as named by Dan Durrie, MD) make a comeback. In the past I have written extensively about the introduction of LASEK into refractive practice. According to recent conversations with Dave Harmon of MarketScope, surface ablation (PRK and LASEK) now account for between 2% and 3% of refractive procedures. This could increase dramatically if it is shown that surface ablations produce better results with customized ablations.

There is no question that customized ablation will be the wave of the future. It will provide better outcomes for previous poor results (decentered ablations, small optical zones, etc.) and produce better quality of vision with improved contract sensitivity and night vision. It will also reduce the need for retreats dramatically, as Manus Kraff, MD, said, "from about 10% down to less than 3%".

In questioning others about custom vs. classic, I asked how many of the patients coming into their practices and being evaluated on wavefront diagnostics had higher order aberrations that could be effectively treated with custom LASIK. Dr. McDonald estimated perhaps 20% of her patients, while Dr. Scott MacRae thought the split was more like 33% with higher order and 67% with lower order alone.

Further, improvements in diagnostics are also under development. VISX, with the aid of 20/10 Perfect Vision, is developing an adaptic optics version of its WaveScan. This will eliminate the need for the PreVue lens, wherein a customized ablation is put onto a plastic disc that can be mounted on a lens set and presented to a patient to show the improvement in vision that could be obtained with customized ablation. In the adaptic optics version, the improvement will be built into the WaveScan device and the patient can be shown the improvement in vision immediately while still sitting in front of the WaveScan. According to Julian Stevens, MD, Nidek and others are also working on this type of technology, along with research at the University of Zurich.

Improvements are also coming in the laser platforms. Although first promulgated by LaserSight (but not fully implemented into the U.S. market), faster small spot scanning lasers with matched faster eyetrackers are coming. Led by WaveLight's Allegretto, Schwind's ESIRIS, and Carl Zeiss Meditec's MEL 80, these lasers will provide shorter ablation times and better outcomes for normal eyes with lower order aberrations.

To put Alcon's custom ablation approval in perspective, the approval label was for up to -7 diopters of myopia, with a 0.5 diopter of astigmatism (as measured by manifest refraction). However, according to several doctors that we spoke with, patients with up to 1.5 diopters of astigmatism, as measured on the LADARWave diagnostic, can be treated. Higher astigmatism approval is not expected from the FDA for 4-6 months. But, according to Dan Durrie, MD, when questioned about the relatively low amounts of astigmatism approved, he said, "that would encompass 40%-50% of my patients".

Bausch & Lomb and VISX have both filed for custom ablation approval, with the FDA expected to give marketing approval to both sometime in the first half of 2003. Since both companies have filed for myopia with astigmatism, once they achieve approval, the playing field should be level for all three major companies.

As shown in two tables(1,2) produced following the meeting, it appears that the quality of the custom ablation data from the four competing firms for the U.S. market does not give any competitive advantage. But, since VISX has the largest installed base of laser systems, and already has its WaveScan in the hands of better than 80% of its laser owners, it may have a marketing advantage.

1. Comparison of Laser Systems for Customized Ablation, Source: Company information and Spectrum Consulting, November 2001.

2. Comparison of Wavefront Diagnostics, Source: Company information and Spectrum Consulting, November 2001, updated October 2002.

(Anyone wishing to obtain a copy of either table should request it from me via email.)

Customized Ablation #7: ASCRS Report: What's New in Customized Ablation and A New Treatment for Hyperopia and More

This is the7th of a series of eight articles chronicling the development of Customized Ablation or Wavefront Directed Lasik. This column was written following the 2002 ASCRS meeting and was published in the August 8, 2002 issue of Ocular Surgery News.

ASCRS Report: What's New in Customized Ablation and A New Treatment for Hyperopia and More

Irving J. Arons
Managing Director
Spectrum Consulting

Much has happened since the last time I addressed the subject of customized ablations in January (my AAO reports in the January 1st and 15th issues of OSN). More thought has been given to the inherent problems -- some of which are now starting to be addressed -- and more data has been collected by several of the companies involved in wavefront-guided custom ablation. As I wrote in January, the results with "classic" LASIK have gotten much better thanks to improved lasers, trackers, and keratomes. Most patients today can obtain uncorrected visual acuity close to or better than 20/20. But wavefront-guided ablations appears to offer even more -- once the problems are solved.

Wavefront Issues

In a recent article ( "Wavefront-guided ablation: What Are the Obstacles to Implementation?", Refractive Eyecare for Ophthalmologists, April 2002), several ophthalmologists addressed some of the issues remaining to be solved. Ron Krueger listed some of these: 1) proper registration of the wavefront information to the laser and its tracking system; 2) wound healing issues -- will the process of healing obliterate the lasers' fine corrections? 3) biomechanical changes in the cornea, especially due to flapmaking in LASIK; 4) the reliability and reproducibility of the wavefront information itself; and 5) defining ablation patterns that truly correct the wavefront pattern.

In ablating the cornea to correct aberrations using wavefront guidance, we are dealing with minute corrections. Such things as the angle at which the pulse strikes the cornea may make a difference in the effect. And, there are hardware and software issues to be addressed. Dr. Krueger believes that there is no single obstacle, but an array of challenges that need to be addressed one step at a time.

In the same article, Marguerite McDonald discussed the unpredictable biomechanical changes induced by the microkeratome cut, that in turn alters the wavefront map in an unpredictable way. That is one of the reasons driving the renewed interest in PRK and LASEK, and why some experts are discussing the possibility of a two-step LASIK procedure, in which first the flap is made, and several weeks later the wavefront diagnostic is taken and the ablation performed.

Registration of the wavefront data was discussed by Dan Durrie (and Marguerite in one of her ASCRS presentations ["Importance of Tracking, Centration, and Registration in Custom Ablations," Marguerite McDonald, MD, ASCRS, Philadelphia, June 2002]). Dr. Durrie noted that the wavefront diagnostic was done on a seated patient, and then was attempted to be transferred to a supine patient some time later. As he discussed, it has been challenging just to center the ablation properly and to maintain orientation in the face of cyclotorsion from the patient's change in posture. With custom ablation the challenge is to position the ablation perfectly, time, after time, after time.

With both the Alcon LadarVision system and the B&L Zyoptix with which he works, he has nothing to confirm that he is in the right place when he starts the ablation. What he would like to see is technology that not only confirms the accuracy of the registration, but that actually performs the alignment and locks it into place. As he noted, this is a quantum jump from current eye tracking.

"What's needed for custom ablation is a failsafe device that will align the ablation pattern with the eye and not let the laser operate unless and until the two are perfectly registered," he said.

Another note of caution was provided by Omar Hakim. He discussed the changing basis of the wavefront, stating that the wavefront was dynamic, changing almost on a moment-to-moment basis. It changes with pupil size and accommodation, and it evolves in other ways over longer periods of time as the eye matures and ages. Thus, a depiction at a point in time may not ideally depict what may happen at a later date.

"The wavefront we are looking at is the product of multiple variables that will differ over time. It is a static representation of a dynamic phenomenon." He suggests that the use of an adjustable corneal inlay in tandem with an adaptive technology, such as liquid crystal chemistry, might be able to create a dynamic wavefront correction.

Wavefront Issues

Dick Lindstrom addressed the biomechanical changes and wound healing processes that occur during LASIK. He noted that it might be difficult to correct the 1-5 micron higher order aberrations when the microkeratome induces 6-12 microns of aberration into each cornea in an unpredictable fashion. And, the final arbiter of corneal wound healing is the corneal epithelial cell -- which is 6-8 microns thick.

As he noted, "One epithelial cell in the wrong place induces more aberration than we are aiming to correct." But as he further noted, "We should not be too pessimistic. This technology is still in its infancy."

Marguerite McDonald, MD, in her ASCRS presentation noted that as the complexity of the correction increases, the requirements for centration, registration and tracking become more stringent. With just a 10° misalignment with cyclotorsion, a second order cylinder correction results in a 30% residual error. The same misalignment for a sixth order correction leaves a residual correction of 100%, with no impact on the desired correction.

She concluded, "While centration, registration and tracking are important for all procedures, they become even more so for customized treatments, especially when complex higher order corrections are attempted."

Manufacturers Addressing Problems

With all of that said, where are we today? Many of the problems noted above are being addressed by the laser manufacturers. Several have already addressed the problems of registration and cyclotorsion, some are also beginning to address the problems induced by the flap with intraoperative pachymetry which accurately measures the real thickness of the flap and the depth of ablation in real time.

In his opening remarks at the VISX/EyeWorld Symposium on "Wavefront Diagnostics, Outcomes and New Technologies, held during the ASCRS meeting, Douglas Koch, MD, put it into perspective, "20/20 was the minority outcome during the early days of PRK/LASIK in the 1990s, today 20/20 outcomes are the majority, while in the future, with the advent of wavefront guided ablations, 20/20 outcomes will be the minimum standard!"

Innovations

In the future, ophthalmic surgeons can look forward to some exciting innovations. Companies such as Asclepion-Meditec (soon to be part of Zeiss Ophthalmics and renamed Carl Zeiss-Meditec) and WaveLight have begun incorporating tissue saving and prolate optimization algorithms into their computer programs driving their lasers. Asclepion introduced its CRS-Master product at ASCRS. This product combines topography and wavefront in an all inclusive workstation with a new sophisticated software package which can be directly linked to the Meditec excimer laser. It allows the surgeon to integrate flap data, corneal thickness, pupil size, topography and wavefront data to define the ideal ablation profile for each eye. The program includes a tissue saving mode, and a prolate and night vision optimization mode, all built into its algorithms.

Nidek, in its newest incarnation of the EC-5000, the EC-5000CXII, (to be introduced this fall) has added an improved, faster responding four-beam infrared eye tracker, along with precision alignment and pupil registration of the undilated eye, a new cyclotorsion error correction algorithm, and the multispot ablation (called MultiPoint by Nidek) that was announced at last fall's AAO meeting, all combined with its combination wavefront and topographical diagnostic, the OPD scan.

VISX has also developed an iris registration cyclotorsion feature for their Star S3 laser tracker. And, as noted above, Schwind is among the first excimer laser producers to link online pachymetry using optical coherence tomography (OCT) with their laser, to intraoperatively visualize the actual thickness of the flap (rather than the theoretical thickness), the depth of ablation, and residual corneal thickness. This enables the surgeon to determine how much tissue has been ablated, and how much residual stromal/corneal thickness remains. The Sirius pachymeter, linked to the ESIRIS laser, allows real-time online visualization of the various stages of the LASIK treatment. (It should be noted that Haag-Streit also produces a corneal pachymetry system, the HS Pachymeter, which can be used in a similar fashion to the Schwind Sirius pachymeter (which I believe comes from Zeiss Humphrey), for inline, real-time optical low coherence reflectometry, to measure corneal thickness to a precision of 1 micron. Haag-Streit said it was working with at least two laser manufacturers who are evaluating its system (believed to be WaveLight and perhaps VISX).

VISX also announced just prior to the ASCRS meeting that it had signed an agreement with Tracey Technologies to market the Tracey Visual Function Analyzer (VFA) ray tracing device, along with the 20/10 Perfect Vision WaveScan aberrometer, to enable refractive surgeons to evaluate both normal eyes (with the WaveScan) and abnormal eyes (with the Tracey VFA), increasing the range of eyes that can be evaluated and treated. VISX has also licensed the Ruiz multifocal patents for the treatment of presbyopia, using its Contoured Ablation Pattern (CAP) procedure, already available on its Star S3 laser for treating astigmatism. Initial trial data on 23 eyes was reported at the meeting. The ablation pattern forms an aspheric cornea giving good vision throughout the visual spectrum (near, intermediate and at distance).

Competition for "Bladeless" flap production

A new entrant showed its wares in the race for "bladeless" flap refractive surgery. 20/10 Perfect Vision displayed its new femtosecond laser in competition with IntraLase. The difference between the two laser systems appears to be the fact that 20/10 Perfect Vision intends to couple its laser with its wavescan aberrometer. In the race for bladeless flaps, 20/10's laser is programmed to produce curved/contoured flaps (to preserve the natural shape of the cornea). The femtosecond laser is capable of both stromal lenticle formation and removal, and of intrastromal ablation, with cutting open the stroma. Because of gas formation within the stroma, the refractive effect may be limited to custom treatments of about two diopters of correction. For higher corrections, it may require a separate treatment sometime after the first treatment has healed. Intrastromal corrections are expected to be done for myopia, hyperopia and for presbyopia (via monovision).

Advances with LASEK

In another attempt to alleviate the effects of the microkeratome-created flap, there were several new LASEK techniques discussed at the meeting. These were in addition to Marguerite McDonald's gel-assisted LASEK technique, which I wrote about in my AAO roundup in January. The new techniques, again to preserve the epithelial tissue included hydrodissection (Richard Rashid, MD) with either BSS solution or the use of Genteal (or even Genteal Gel, in some cases), LASEK viscodissection (David Langerman), and Ioannis Pallikaris's new sub-epithelial separator device, the SES. This is an automated microkeratome-based device for use with his sub-epithelial Lasik procedure (or EpiLasik, as others have called it). The device, along with a suction ring, creates an epithelial flap without the need for using alcohol, that allegedly results in faster healing and less pain for the patient. The SES is not currently available in the U.S., but is expected to be on the market international by Ciba Vision in early 2003. Dan Durrie has even suggested a new name for LASEK, to avoid its confusion with LASIK. He advocates calling LASEK procedures "Advanced Surface Ablation".

A New Treatment for Hyperopia (and beyond)

With its recent FDA marketing approval, Refractec held a symposium to introduce conductive keratoplasty (CK) to ophthalmologists. At the symposium, held in conjunction with Ophthalmology Management, Dan Durrie, Robert Maloney, and Marguerite McDonald provided some very interesting information about the use of CK to treat astigmatism (Durrie), presbyopia (Maloney), and hyperopia -- the U.S. clinical trial results (McDonald). Dan Durrie led of the session discussing his experience in using CK for treating astigmatism. What he found was that he could actually adjust the amount of correction intraoperatively by viewing the reflected ring formed by the cornea as the probe was applied in different quadrants.

Robert Maloney discussed how the ViewPoint device could be used to provide near vision via monovision to correct for presbyopia. With the patients he has treated, the effect looked good out to 3 years. Although the device had only been approved for hyperopia without astigmatism, it is being used successfully off-label for treating astigmatism, presbyopia, and over and under corrected LASIKs. Dr. Maloney noted that there was a very fast learning curve and was fool proof to use. In his presbyopia trials, after nine months, 79% of his patients were seeing 20/20 J2; 83% 20/25 J3; 87% 20/32 J5; and 91% 20/40 J6. Stability was achieved in within 2-3 weeks.

Dr. Maloney also described how the heating effect of CK was different from what was achieved with LTK (using the Sunrise laser). In a thermal effects study done by A.J. Welch's group at the University of Texas, the heating zone profile produced by the ViewPoint needle probe was more uniform and, thinner, and deeper (a column of heating 250 microns wide and 80% of the cornea deep), while the LTK laser pulses produced a much wider heating zone that concentrated in the upper stroma. That might explain the anticipated less regression with the CK device compared to the LTK. And, in fact, when Dr. McDonald was asked about the "temporary" label given to Refractec by the FDA, she said it was because of their previous experience, and it would probably be removed when Refractec provided its two-year data to the agency.

Dr. McDonald discussed the FDA trial data that led to the .75 to +3.00 diopters of hyperopia approval. At 12 months, 54% of patients achieved 20/20; 74% were 20/25; and 91% were 20/40 or better. As for stability, there was 0.9 of a diopter loss in the first 3-6 months, 0.03 diopters in the 9-12 month period, and only 0.04 diopters during months 12-24.

There is, however, one caveat to consider about the use of ViewPoint CK for treating hyperopia. Most low hyperopes are comfortable with their vision. It is only when they become presbyopic that they begin looking for alternatives. Thus, the real problem to be solved with CK is presbyopia, not low to moderate hyperopia, along with some degree of astigmatism (and over/under corrected LASIKs). But that said, because of the low price of the device, the ease of its use, and its safety record, once the "temporary" label is removed, I would expect to see widespread use of this device as an alternative to hyperopic LASIK.

Customized Ablation #6: AAO Refractive Pre-meetings Focus on LASIK, LASEK

This is the 6th of a series of eight articles chronicling the development of Customized Ablation or Wavefront Directed Lasik. This column was written following the pre-meetings before the 2001 AAO meeting and was published in the January 15, 2002 issue of Ocular Surgery News.

Technology Update

Irving J. Arons
Spectrum Consulting

AAO Refractive Pre-meetings Focus on LASIK, LASEK

[LASIK results are improving with active eye trackers. LASEK may provide better results with wavefront-guided ablation. Other options seem far off in development.]

As I have done for several years, I attended the refractive pre-meetings held by the International Society of Refractive Surgery (ISRS) and the Refractive Surgery Interest Group (RSIG), prior to visiting the AAO exhibit halls. This year, after looking at both programs, I decided to spend most of my time at the ISRS Fall Refractive Symposium. That two-day program was jam-packed with sessions of interest, and I had to pick and choose carefully in order to get a good sampling of what is new in refractive surgery.

First Day of ISRS

Just to give you an idea of what I mean, the opening morning alone at the ISRS meeting had three sessions I wanted to attend -- Thermokeratoplasty & Non-excimer Lasers (covering laser thermokeratoplasty using both the Sunrise [holmium] and Rodenstock [diode] lasers, the IntraLase femtosecond laser, and conductive keratoplasty using the Refractec Viewpoint CK system); Laser Delivery and Profile Debate (covering eyetrackers, treatment zones sizes, and results obtained with several of the laser systems using the new eyetrackers; and the latest version of Catch the Wave -- with presentations by most of the refractive laser companies describing the latest versions of their lasers and diagnostics. (The early morning presenters were Alcon and Nidek.) And that was just the early morning sessions.

The late morning sessions covered the use of LASIK for correcting hyperopia with and without astigmatism (which also snuck in the latest Leeming Survey of Trends in Refractive Surgery in the United States: The 2001 ISRS Survey -- more on this later), and a session on microkeratomes, with nine speakers discussing their favorite keratome. The Catch the Wave presenters during this session were VISX and LaserSight.

The early afternoon session had a discussion on refractive IOLs, with several speakers debating the merits of use of phakic IOLs, and including a session on a new laser adjustable IOL; a session on Worst Case/Best Save Video Groundrounds, which included several presentations on LASEK; while Catch the Wave continued with three of the small spot scanning laser presentations (by Asclepion-Meditec, WaveLight, and Bausch & Lomb).

The late afternoon included a discussion of LASIK Complications and a session titled Diagnostic Wavefront/Optical Aberrations, which included a face-off between the various measurement systems -- Hartmann-Shack aberrometry (Alcon, Asclepion-Meditec, Bausch & Lomb, and VISX), ray tracing (Tracey), scanning slit refractometer (Nidek), and Tscherning (WaveLight and Schwind); versus corneal mapping using AstraMax (LaserSight), Orbscan (Bausch & Lomb), and other topographers. The real question asked -- is wavefront measurement necessary, or is topographical measurement enough?

And that was just the first day of the meeting.

Second Day of ISRS

On the second day, the early morning sessions included meetings on Wavefront Technology and Custom Ablation -- a face-off of the various laser systems and their approaches to wavefront-guided custom ablations; and another section on topography versus wavefront. The competing early morning session was on refractive implantable devices, including talks on Intacs, intracorneal implants for hyperopia (the PermaVision lens from Anamed), the Ferrara intracorneal rings, and talks on implantable IOLs for hyperopia.

The late morning sessions included Presbyopia Correction, with discussions of scleral bands (Presby Corp.), laser ablation (SurgiLight), anterior sclerotomy, myopic LASIK with monovision, LTK for monovision, and talks on two of the accommodating IOLs (the AT-45 from C&C Vision and the 1CU from Human Eyes); along with a second session on LASIK Complications.

The afternoon sessions included one on management issues, Re-inventing Yourself as a Refractive Surgeon: What it Takes in 2001; and a session on LASIK Enhancement and Lamellar Surgery.

In looking over the RSIG meeting program, a number of the same topics were covered, including LASIK techniques and complications; PRK and Intracorneal Implants; Presbyopia; Surgical Correction of Hyperopia; IOLs in Refractive Surgery; and Refractive Lasers and Aberrometers.

Overview

In order to cover as many bases as possible, I have organized this article to include the latest information by type of correction, i.e., what is happening in the correction of myopia, hyperopia, and presbyopia. The report mainly covers laser approaches, but includes, where appropriate, non-laser techniques under development to replace/displace the laser approaches, such as inlays (Permavision from Anamed) and heated tips (ViewPoint CK from Refractec) for hyperopia, and accommodating IOLs and surgical techniques (Presby Corp.) for presbyopia. Included in the laser discussions are excimer-based procedures, as well as those being done with holmium (Sunrise's LTK), erbium (SurgiLight's presbyopia reversal), and femtosecond devices (IntraLase's microkeratome replacement today, and possible refractive application in the future).

Current Correction of Myopia

According to the latest survey data from Market Scope, close to 94% of ophthalmologists are using standard or "classic" LASIK for correcting low myopia (up to 3 diopters); almost 99% use LASIK for moderate myopia (up to 5 diopters); while 91% use it for high myopia (over 7 diopters) -- the rest using phakic IOLs (5%) or some other technique. The percentages are just as high for correcting myopia with astigmatism. Thus, the question to be answered at this year's meetings was, is there anything coming along that might replace "classic" LASIK?

And there were some answers. The use of eyetrackers are leading to some spectacular results with LASIK. The newer laser systems with improved eyetrackers seem to be obtaining excellent results. As shown in my accompanying Customized Ablation article (#5 in this series), the reported results for just two of the newer laser systems, the VISX Star S3 with Active Trak, and the Wavelight Allegretto, also with an active infrared tracker, compare very well with the data obtained with the initial results obtained in the wavefront customized ablation trials reported to date. The use of eyetrackers leads to better centration (with no decentration) and the ability to place blend zones where they add to better quality vision (reduction of glare and halos in night vision).

Future Correction of Myopia

The next question is how much better will the results be with either wavefront or corneal topographers added to the systems. That answer was not as clear. Two of the companies have topography systems combined with their wavefront devices -- Bausch & Lomb's Zyoptix Zywave wavefront along with its Orbscan IIZ topographer and Nidek's NAVEX OPD-Scan, which combines topography with retinoscopy to provide total eye aberrations. In addition, LaserSight has developed its AstraMax stereotopography system which is linked to their new CIPTA software to provide oblate corneal ablations. (Only Alcon and VISX do not have a built-in topographer.) I was not able to obtain clinical data on these systems, but scuttlebutt in the halls of the meeting suggested that all were providing improved results when compared to "classic" LASIK.

All of the laser manufacturers now have some sort of active eye trackers, and all but LaserSight have working wavefront devices. So far, only the Asclepion, Schwind, WaveLight and Alcon systems are directly linked to their lasers. But all companies have plans to do that and, with the systems in use today, it is a simple task to perform the wavefront analysis, copy it to a disc, and place the disc into the laser to perform the ablation. Also noted in the table is the status of U.S. clinical trials for custom ablations. Alcon and B&L (with their international data) appear to be in the lead, with VISX about six to eight months behind. All of the other companies are still in their planning stages.

So, the real question is -- if "classic" LASIK with the improved laser systems is working so well, do we need wavefront? And, as I've said, that answer is not clear. Wavefront-guided ablations will be used to correct previous problems, including decentered ablation, uncleared central islands, and irregular astigmatism. It is expected to improve the quality of vision, especially for those people suffering from poor night vision, and to minimize induced aberrations, as well as correcting higher order aberrations such as third-order aberrations coma and trefoil. But, there is the problem of how much higher order aberrations should be corrected? As related in Customized Ablation article, in a study of Navy Top Gun pilots, a comparison of higher order aberrations showed that those pilots with 20/12.5 acuity had some degree of coma, while those with normal 20/20 acuities, had less. Would we turn 20/12.5 pilots into 20/20 pilots if we corrected their higher order aberrations?

The first answers are ambiguous. As reported by Coleman Kraff, MD, some surgeons are getting excellent results, but others haven't yet hit their mark. (See the Postop Wavefront Outcomes table in the Customized Ablation article.)

In order for wavefront-guided ablations to provide for minimized individual aberrations, there is the need to accurately register the eye between the capture of the diagnosis and the treatment, and preferably this should be done in three axes. There appears to be a lot of work ahead before wavefront-guided ablations become the norm.

One last point. LASIK, even with wavefront, gives more aberrations rather than fewer. PRK, as shown in Marguerite McDonald's study of wavefront-guided PRK vs. LASIK studies last year showed that her PRK patients routinely had better acuities than did her LASIK patients. Thus the impetus for LASEK. But, the results reported to date for LASEK have been a mixed bag, some doctors reporting excellent results, while others have reported problems due to the alcohol solution used to lift the epithelium causing cell deaths, haze, and regression.

Now, as reported in the Customized Ablation article, Dr. McDonald has done it again. In her Binkhorst Lecture acceptance speech, she described what she calls "gel-assisted LASEK". Using hydroxypropylcellulose gel, she found that she could "stiffen" the epithelium and lift it from its stromal bed, and then cut it into quadrants that can be lifted outward away from the ablation zone, allowing PRK to be performed on the stroma. Again using the gel, she was able to push the epithelium quadrants back onto the cornea, and using a bandage contact lens, get re-epithelization without cellular loss. She believes that flap-free LASEK is a safer alternative to LASIK.

LASIK/LASEK Refractive Alternatives

To quickly answer the question, what lays beyond the answers shown above? Not much. Intralase with its femtosecond laser to perform intrastromal ablation -- the removal of tissue within the stroma by making two passes at different levels -- is still quite a ways off. Previous attempts to do this by both Intelligent Surgical Laser (picosecond laser) and Phoenix Laser Systems (with a Q-switched YAG) in the late 1980s were unsuccessful. As far as I can tell, only early experiments have been performed, and it will probably be some time before human trials are conducted. The company strategy is first to establish a beachhead as a microkeratome, then seek approval to treat presbyopia, and finally to go after myopia approval.

I do not see clear lens extraction, especially for low to moderate myopes as an alternative to refractive surgery.

As for the solid-state laser from Q-Vis, after speaking to company representatives at the meeting, it appears that this company is a long way from establishing a beachhead in the U.S. The company is just starting Phase III clinical trials, so is at least 12-18 months away from filing their PMA. There is also the question of carcinogenesis caused by the 213 nm wavelength. As I recall from my early days in excimer refractive surgery, that question had been raised when JT Lin first proposed a solid-state quintupled YAG operating at 213 nm. I'm not sure it was ever fully resolved.

There is however, a fly in the ointment. Ciba Vision has recently had a new extended wear contact lens approved, and Bausch & Lomb has followed suit, with a second approved lens. These could prove to be viable alternatives to surgery. Back in the mid-seventies, when the first extended wear lenses became available, they took the public by storm -- some of you may recall the CooperVision TV ad that proclaimed -- "I can see beyond my bedcovers!" However, corneal ulcers and other problems soon stopped that generation of lenses in their tracks. But, these new lenses are truly oxygen permeable and have probably overcome all of the earlier problems. So, I advise you to carefully watch how well they are accepted.

Current Correction of Hyperopia

Again, according to the Market Scope Survey of Refractive Surgeons, almost every surgeon chooses LASIK for the correction of low or moderate hyperopia, with or without astigmatism -- in the high 80%s. Only about 8% of surgeons use Sunrises' LTK system, about 1% still use PRK, with 4% (for low hyperopia) and 16% (for moderate hyperopia) choose some other means (undefined). Only for high hyperopia correction, do 20% of surgeons turn to phakic IOLs, while 21% still use LASIK, and 63% choose some other means.

The ISRS Survey showed similar results. For +1 hyperopes, 70% of survey respondents chose LASIK, 17% said they would use either LTK or CK; for +3 hyperopes, 84% chose LASIK and only 2% said they would use LTK or CLE (clear lens extraction); for +5 hyperopes, 29% chose LASIK, 39% said their choice was CLE, while 30% said they would wait for something else.

Based on what I picked up at the sessions, the two laser systems approved for hyperopia (LadarVision and Star S3), with their working eyetracker systems, are achieving very good results for hyperopia and hyperopia with astigmatism. The feeling was that these newer systems were giving 3 to 4 times improvement over those systems without the eyetracker. For that reason, few ophthalmologists appear to be interested in trying the Sunrise LTK system, which has apparently fallen out of favor. There was however, much interest in the Refractec ViewPoint CK system, especially at its very low price point of $45,000 for the unit and approximately $100-$150 for the disposable tips, one used for each eye.

Future Correction of Hyperopia

On the horizon, the only other new means for correcting hyperopia is the Anamed PermaVision Lens. This unique 78% hydrogel lenticle, with the same refractive index as the cornea, and which is only 30-60 microns thick, appears to provide adequate fluid and nutrient flow to keep the cornea healthy. It is used for correcting from +1 to +6 diopter of hyperopia, by opening a flap in the cornea, inserting the lens, and closing the flap. In the international clinical study, in sixty patients, the average starting spherical manifest spherical equivalent was +3.52 diopters. Of 14 patients examined after six months, the SME was down to +0.58 diopters. Immediately postop, the patients were about -0.5 myopic, and they drifted to plano over two to three weeks.

An inversion problem with insertion of the lens has apparently been overcome with the use of a new applicator delivery system. The company has received CE approval for marketing in Europe. U.S. clinical trials are expected to begin by the end of this year.

I did not sit in on any of the sessions covering the phakic IOL lenses, and therefore, will not comment on them in this report.

Current Correction of Presbyopia

As listed by John Hunkeler, there are a bevy of options for the correction of presbyopia: these include monovision, pseudo accommodation, and multifocal vision. Among the surgical options are monovision LASIK, multifocal corneal ablation, monovision with LTK or CK, scleral relaxing incisions, scleral expansion bands, laser scleral ablation, and lens exchange using the Array multifocal IOL, and accommodating IOLs. Of course, he left out no-line eyeglasses and multifocal contact lenses.

Of all the options, other than LASIK monovision, probably the insertion of the Array multifocal IOL has had the best results to date. While the jury is still out on the accommodating IOLs from at least three manufacturers -- the AT-45 CrystaLens from C&C Vision, the Human Optics 1CU, and an unnamed lens under development by Quest Vision.

Future Correction of Presbyopia

Of the non-monovision surgical options, ancillary scleral relaxation incisions don't work. Just cutting the sclera, in an RK-like fashion, quickly regresses and leaves the patient with no change in near vision. Scleral expansion bands do seem to provide some near vision ability for about 70% of the patients tried to date. While laser scleral ablation, which appears barbaric when witnessed, has had good results in some doctors hands, others have not fared as well. More trials are needed with both of these latter techniques to see if they will really work in the non-specialist's hands.

Customized Ablation #5: The Wave Moves Forward --- but a new LASEK procedure may prove to be the winner!

This is the 5th of a series of eight articles chronicling the development of Customized Ablation or Wavefront Directed Lasik. This column was written following the 2001 AAO meeting and was published in the January 1, 2002 issue of Ocular Surgery News.

Customized Ablation: The Wave Moves Forward --- but a new LASEK procedure may prove to be the winner!

Technology Update

Irving J. Arons
Spectrum Consulting

Over the past several years, beginning in June 1999, I have written extensively on the coming of customized ablations based on wavefront diagnoses. All of the laser companies have initiated international trials and several have now begun their U.S. clinicals, including Alcon, VISX, and Bausch & Lomb. LaserSight and Nidek plan to begin U.S. trials by year's end, while WaveLight and Asclepion-Meditec plan to begin U.S. trials early next spring. (Schwind Eye-Tech Solutions does not intend to enter the U.S. market.) That all begs the question -- is wavefront diagnostics necessary to get good results with today's laser systems? My eyes were opened to the great results being reported by several laser companies using standard or "classic" LASIK on the new upgraded laser platforms, especially with low to moderate myopes. With the vast improvement in eye trackers now used with today's improved laser systems, it is almost routine for most refractive surgeons to bring better than 90% of their low to moderate myopes to 20/20 UCVA, while having a large proportion obtaining even better uncorrected acuities of 20/16 or better. (See the early results obtained for two laser systems with improved eye trackers shown in Tables 1 and 2.) So, I ask again, is wavefront necessary? And the unequivocal answer is YES!

While not yet producing overall rates of 20/20 vision better than that is being obtained by "classic" LASIK yet, wavefront-guided ablations are being and will be used to correct irregular astigmatism and to correct past mistakes given either by decentered ablations, central islands, or other problems such as caused by scars or flaps. In addition, by correcting for spherical aberrations and some degree of higher order aberrations, the quality of vision can be improved, leading, for example, to improved mesopic or night vision. Then of course, there are those who desire "supervision", i.e., 20/16 or better UCVA. Those might include athletes, pilots and others for whom work-related super sharp vision is important. However, the vast majority of people will be satisfied with ridding themselves of eyeglasses or contact lenses for improved general distance vision. (Presbyopia is still mostly an unsolved problem, but as many as 85% of patients can do, and will do well with modified monovision -- with their dominant eye corrected for distance and the non-dominant eye for near.)

Wavefront diagnoses linked to laser ablation may not be the end all. Recent wavefront analyses of "top gun" pilots, whose vision was 20/12.5, was compared to other "top gun" pilots with normal 20/20 vision. It turned out that the wavefront analysis of the 20/12.5 pilots group showed significant amounts of higher order aberrations (primarily coma, a third order aberration) compared to the normal 20/20 group. If these supervision eyes had been corrected to rid them of the coma, it is likely they would have become 20/20 normal vision pilots! So, maybe some higher order aberrations are not necessary to correct. We still have a lot or work ahead of us to know what should and should not be corrected for.

In a debate held as part of the WaveLight meeting for their investigators, the question was asked, Wavefront or Not? And, although the ophthalmic audience in the end voted in favor of wavefront-guided ablation, this was probably because of the stature of the speaker (Prof. Theo Seilor), while the results obtained in the U.S. WaveLight clinical trials for the Allegretto laser without wavefront coupling (see Table 2, above), as presented by Guy Kezarian, were truly remarkable, and I would have been hard pressed to vote in favor of the need for wavefront diagnosis.

The Re-Emergence of LASEK

There has been quite a debate whether LASEK would result in a re-birth of PRK. Since I first wrote about this emerging technique a year ago, several refractive surgeons have turned to this procedure as their primary mode of surgery (Dan Durrie and Thomas Claringbold being among them). But, others have questioned the applicability of the procedure, especially with the epithelial cell death caused by the use of the alcohol solution to stiffen and loosen the epithelium from the underlying stromal bed. Well, I have good news.

My interest in writing about LASEK was piqued after hearing the results that Marguerite McDonald presented at the 2000 AAO meeting, where her Custom Cornea PRK patients had shown better results than those treated with LASIK following wavefront diagnosis. As she reported, her PRK patients eyes had much better UCVAs than did the eyes of her LASIK patients. This was probably due to the induced aberrations caused by creating the flap for LASIK. At the same meeting, actually at that year's ISRS Symposium, I first heard about Dr. Massimo Camellin's LASEK procedure, as reported by a couple of presenters. The combination of a better way of doing PRK, along with Dr. McDonald's better outcomes with customized PRK, led me to report on LASEK as a possible, even better way, of performing customized PRK.

Following the literature since my article, LASEK results in most other surgeons's hands have given mixed results. Then the wake up call came. In her Binkhorst award acceptance lecture at this year's AAO meeting, Dr. McDonald described a new LASEK approach and reported on the first results of patients she had treated with, as she described it, "gel-assisted LASEK". Instead of using alcohol to obtain epithelial peeling (with its accompanying death of many of the epithelial cells), she has found a better way to lift the epithelium. Using hydroxypropyl cellulose gel she can get both stiffening and separation of the epithelium, without causing cellular death. After using a specially designed spatula, and another specially designed tool for gel application, she is able to lift the epithelium and cut it into quadrants and move the quadrants out of the way for performing PRK onto the denuded stroma. Following the ablation, she is able to replace the epithelium (again with the use of the gel), and to protect the eye with a bandage contact lens during re-epithelization. Dr. McDonald reported that she had treated 40 eyes of 21 patients (two had only one eye operated on), with four eyes being treated for monovision, and not included in the UCVA study. With only 13 eyes available for two-week followup, she reported 85% were 20/20, and 100% were 20/25 or better. Now that's pretty good for a two-week followup for customized LASEK/PRK!

So, LASEK, that is gel-assisted LASEK, lives, and could be the answer to truly improved custom ablations!

Customized Ablation #4: The Wave Moves Forward -- But Consider LASEK!

This is the fourth of a series of eight articles chronicling the development of Customized Ablation or Wavefront Directed Lasik. This column was written following the 2000 AAO pre-meetings and was published in the January 1, 2001 issue of Ocular Surgery News.

Customized Ablation: the Wave Moves Forward – but Keep an Eye on a Newly Developing Technique – LASEK!

Spotlight on Ophthallmic Lasers

Irving J. Arons
Managing Director
Spectrum Consulting

As I have written over the past two years (most recently in the February 15th and August 1st, 2000 issues of Ocular Surgery News (OSN)), the outlook for performing customized ablation, based on wavefront or ray tracing diagnostic technologies, continues to be bright. At this year's ASCRS, we saw the first indications that the diagnostic technology was moving forward, and now, at the recent ISRS (International Society of Refractive Surgery) and RSIG (Refractive Surgery Interest Group) pre-meetings held in conjunction with this year's AAO meeting, we learned of the results of the first customized treatments and the approaches each company was taking.

One thing appears evident. Correction of higher order aberrations is not going to be easy. There are still many unknowns along the path to achieving "SuperVision", before customized ablations becomes a reality. Although getting closer yet -- as I have written, we are probably still 1½ to 2 years from the reality of customized ablation being used in general practice.

On first blush, and based on early reports, PRK customized treatments appear to provide better results than those obtained from customized LASIK -- see the Summit Autonomous clinical results reported below. If this continues to be true -- primarily because of the influence of the flap, and its unknown (yet) effect on final outcomes, a relatively new procedure, LASEK, or the use of an epithelial flap, followed by PRK, first performed by Dr. Massimo Camellin of Rovigo, Italy, but now being used by several surgeons around the globe, may become the preferred method for producing customized ablations. From what little that has been presented to date, the healing response and restoration of visual stability of LASEK is about seven days, compared to the 1-2 months for standard PRK, and 1-2 days for LASIK. Thus the combination of wavefront (or ray tracing) diagnostic and customized PRK using LASEK could eliminate the unknown effect created by a microkeratome-created flap, and might just prove to be the right ticket to the next advance in refractive surgery.

There is, as with most things, an alternative approach -- two step LASIK. In order to alleviate the effect of the flap, a LASIK procedure would be done in the normal manner first, and then, about a week later, a wavefront diagnostic performed to determine the higher order aberrations yet to be corrected, followed by a "touch up" or enhancement with LASIK to provide the final correction.

It will be up to the marketplace to decide which technique the public would accept -- a one-step customized PRK/LASEK, or a two-step LASIK.

LASEK

So just what is LASEK. As first described in OSN in the March 1, 1999 issue, LASEK, or laser epithelial keratomileusis, is based on the detachment of an epithelial flap via the use of an alcoholic solution that softens the epithelium and allows it to be "rolled" back into a flap, and which can then be repositioned over the ablation following PRK. In use, a pre-incision of the corneal epithelium is made using a trephine with an 80 mm blade, with a blunt portion of about 100° at the 12 o'clock position to circumscribe the flap area. A rotation of about 10° is made to form the incision. Two to three drops of 18%-20% alcohol solution is placed onto the cornea within the marker and left in place for 30 seconds. The area is then dried and thoroughly washed with water and the pre-cut margin lifted with a modified Desmarres spatula and the epithelial flap gently detached, gathered, and folded up at the 12 o'clock position. Epithelial trephination is designed to leave a hinge of about 80-100° at the 12-o'clock position. (A final irrigation with antihistamine is used to reduce any initial release of histamine induced by the alcohol.) Following a traditional PRK treatment, with light smoothing at its conclusion, the epithelial flap is then repositioned with a small spatula.

According to Dr. Camellin, "The epithelial flap is very elastic. It goes back into place easily and smoothly." Following the treatment, a soft contact bandage lens is applied for 3-4 days to keep the flap in place and allow for re-epithelization. Dr. Camellin noted, "The day after, the epithelium is still perfectly transparent and the patients complain of no more than a slight discomfort, comparable, in my experience, to the effects of LASIK." He reported that after 24 hours, the flap was perfectly sealed around the edge in all of his patients. He explained that at this stage, the epithelial flap has a tectonic rather than a visual function. The new epithelium, which regenerated within seven days, enables the eye to reach 100% of visual acuity. After four days after removal of the bandage contact lens, his patients had visual acuities, on average, better than those with traditional PRK, and comparable with LASIK. In his opinion, because of the high dilution of the alcoholic solution, only part of the epithelial cells die and on the epithelium, on the whole, remains vital.

In the July 15, 2000 issue of OSN, Dr. Camellin reported on over one-year's experience with the LASEK technique. He reported on the treating of 249 patients with the technique, of which 204 were myopic, 41 hyperopic, and 29 retreated after PRK haze, radial keratotomy, keratoplasty or LASEK. The longest followup was 14 months. Intraoperative flap management was easy in 60% of the cases, average in 28%, and difficult in 12%. All of the difficult cases involved strong adherence of the epithelium to Bowman's membrane. He found that retreatments were inevitably difficult, although the flap was easily detachable within 3 months, almost as in a primary operation. He believes that this confirms that the presence of a basal membrane reduces scar exuberance and excessive proliferation of new collagen. Postoperative pain appears limited, if any, to the first 24 hours after surgery, with no pain experienced by 44% of patients, some discomfort by 42%, and pain by 14%. He attributes the postoperative pain partly due to the contamination of the conjunctiva by the alcohol solution. He further noted that almost 90% of his patients achieved 80% of their preoperative best corrected visual acuity by day ten following surgery.

At this year's combined meeting, there were at least two papers on LASEK and one poster. At the WRSS meeting, Dr. Sunil Shah of Birmingham England presented on "Alcohol Delamination of the Epithelial Basement Membrane" and Dr. Paolo Vinciguerra of Italy provided, "Laser Epithelial Keratomileusis (LASEK): One-Year Results of a New Excimer Refractive Procedure", while Dr. Chao-Chien Chu had a poster entitled, "Comparison of Laser Epithelium Keratomileusis (LASEK) and Photorefractive Keratectomy (PRK)".

According to his paper, Dr. Shah provided details wherein he treated 178 eyes of 89 patients, with one eye using alcohol debridements and the second eye having the epithelial flap. His results showed that the eye with the flap had a higher UCVA Snellen fraction post-op for the first six weeks following surgery, and then both eyes were equal out for the remainder of the one year followup. In post-op BCVA Snellen fraction, the epithelial flap eye proved better than the PRK eye with debridement after the first week and out for a year. The flap eye also had significantly less haze than did the debrided eye.

In Dr. Vinciguerra's talk, he reported on 432 eyes. According to his abstract (I was not able to attend his talk), 89% of his patient achieved refractive stability within 1-2 weeks, and at 12 months, the Snellen Equivalent was -0.10D ± 0.7D. Haze did not exceed trace and the patients reported only postoperative "grittiness". He concluded that LASEK provides significantly quicker visual recovery and refractive stability than standard PRK, produces practically no haze, and eliminated post-PRK pain.

Dr. Hu's poster compared performing LASEK on 19 patients, and PRK on the fellow eye. The LASEK eyes achieved best UCVA within one month, while PRK eyes did that in about two weeks. LASEK eyes achieved steady-state refraction in one month, and there was no difference in terms of post-operative pain. He concluded that the visual recovery was somewhat slower in the LASEK group, which might have resulted from the disproportional central islands he found in the early post-operative period. (This is surprising as Dr. Camellin has noted that in his experience, the laser should be set at lower values than those normally indicated, as the almost total absence of regression entails a higher correction than that obtained with normal PRK...it is advisable to reduce preset values by 10% when correcting up to 10D of myopia, and 20% for myopia between 10D and 20D.)

Wavefront Clinical Results -- From the "Catch the Wave" WRSS (ISRS) Presentations

Alcon Summit Autonomous

Summit Autonomous appears to be in the lead in terms of U.S. clinicals (although Asclepion-Meditec, WaveLight and Schwind continue to make progress outside of the U.S.). At the Academy, Dr. Marguerite McDonald had treated some 59 patients in two groups. In the first group of 23 eyes, treated beginning in October, 1999, 23 patients were given bilateral LASIK and 13 patients bilateral PRK. Each patient had one eye treated according to the CustomCornea diagnostic, while the other eye was treated according to standard refraction. With six month followup, the myopic LASIK group showed that 85% of the customized eyes achieved UCVA of 20/25 or better, compared to 92% who had the standard LASIK treatment. Similarly, in the hyperopic group, 90% of the conventionally treated eyes achieved 20/40 or better, compared to only 80% of the eyes given custom LASIK.

In the second group of 13 patients given either customized or conventional PRK, 85% of the customized eyes achieved UCVA of 20/20 or better compared to only 65% of the standard PRK eyes. In a third group of 23 patients treated with customized and conventional LASIK, after the algorithms had been adjusted, but with only one week followup, 70% of the customized eyes achieved 20/20 or better, compared to 78% of the conventional LASIK eyes.

Thus, it appears, even with very early data, that there is a decrease in higher order aberrations with customized PRK (46% decrease) compared to only 26% decrease with customized LASIK. Could this lead to a PRK comeback? Especially, when combined with LASEK, as described above.

VISX

At the ISRS/WRSS meeting, Keith Williams, speaking for VISX, presented on four patients who had had previous unsuccessful refractive surgeries, and had undergone wavefront analysis to correct the problems incurred. All four got markedly improved acuity results, albeit after only one week of followup. The patients were first refracted with conventional manifest refractions, and then again with VISX's WaveScan wavefront diagnostic. The surgeon then ablated a plastic lens, the PreView lens, with which the patient could "test" his/her new refraction to determine if it provided better acuity. If the wavefront method was preferable, the patient was treated with a second LASIK, using the VISX Star S3 variable spot scanning laser. Of the four re-treated patients, ranging in pre-op UCVA from 20/30 to 20/200, all achieved improved results, with three achieving 20/15 one week post-op, and the 20/200 patient improving to 20/30, and all were corrected to their best pre-op BCVA. The only negative was that contrast sensitivity was slightly worse post-op. (It should be noted that the PreView lens used by VISX, and shown on the Academy floor, was first used by Asclepion-Meditec, whose AWACS (Asclepion Wavefront Aberration Correction Simulator) process, whereby a wavefront imprint is placed onto an optical plastic slide for previewing a patient's wavefront guided correction. According to company sources from both companies, Asclepion came up with the idea first.)

Bausch & Lomb

Stephen Slade made the case for use of Bausch's Zyoptix system, which incorporates its Zywave wavefront aberrometer and the Technolas 217Z laser. According to Slade, more than 400 patients have been treated to date in Europe, but results on only 32 patients enrolled in a prospective pilot study in Germany were presented. One eye received standard LASIK, while the other received a wavefront-guided ablation. The results showed on average, a one line increase in BCVA in eyes treated with the wavefront-guided ablation. Of the 32 patients, 7 had no difference between the two eyes; 4 had worse BCVA in the custom eye; and the remaining 21 had better BCVA in the custom eye. These early results are promising, but only compared BCVA and not UCVA, to allow a comparison to results with both the Autonomous and VISX systems. B&L hopes to begin its U.S. clinical trials in December.

LaserSight

Jack Holladay described what LaserSight was doing in custom ablation. It turns out that the company is planning to do all of its work with its AstraMax system, which is similar to B&L's Orbscan device, aiming to achieve prolate corneas, with less tissue removal. The AstraMax only provides stereographic topographic diagnostic information, and does not (yet) have wavescan ability.

WaveLight

Professor Dr. Theo Seiler made the case for WaveLight, stating that "SuperVision" was not the main goal, but that correcting almost everyone to 20/15 was probably good enough, while the use of wavefront was most useful for correction of problematic eyes. Wavefront corrects both refraction and aberration. Some of the problems remaining are to achieve centration of the treatment -- aligning the measurement and the treatment, while adjusting for cyclotorsion -- the difference from measuring while sitting and treating while the patient is lying down. He reported on his patients with at least three months followup, achieving no loss of more than 1 line of vision, but getting an increase in RMS error on average of 1.44±0.74, a 44% increase, a suboptimal result. (Is this due to the effect of the LASIK flap?) Standard LASIK results in a 5-25 times increase. What was accomplished, 15% of the patients treated with waveguided ablation achieved 20/10, compared to only 5% of standard LASIK patients; 45% were between 20/16-20/12, compared to 30% of LASIK treated; and 30% achieved 20/20 compared to 50% with LASIK alone. Thus, 80% achieved 20/20 or better with wavefront, while 85% got that correction with standard LASIK. Dr. Seiler reiterated that, at least at this stage in its development, wavefront guided ablation is best used to clean up previous bad results; that it has not yet achieved its potential, but correlates well with BCVA; and, super normal vision may yet be achievable.

The Road to SuperVision -- from the RSIG Meeting

Presentations

Jack Holladay led off the discussions with his "prolate is best" speech, wherein LaserSight, as noted above, plans to use its stereographic AstraMax analyzer to achieve prolate customized ablations. Michael Knorz next described the Bausch & Lomb approach of using its ZyWave and Technolas 217Z system. Marc Odrich than discussed VISX's CAP (topographic -- using the Zeiss MasterVue topographer) method, comparing it with wavefront, with only limited experience. Marguerite McDonald then presented her previously reported results, which showed that PRK waveguided results appear to be better than those achieved with LASIK. And finally, Scott MacRae discussed Nidek's OPD Scan approach, which combines topography with a scanning slit autorefractor/retinoscopy to give wavefront-like results.

Panel Discussion

But the best was left for last, a roundtable discussion where five leading refractive surgeons, Rubens Belfort, Daniel Epstein, Jose Guell, Ronald Krueger, and Michael Lawless debated the merits of wavefront versus traditional corneal topography. Some of the panelists thought that topographical analysis was more relevant and easier to understand, while other thought that wavefront was the future, with topography as an adjunct. Most agreed that wavefront presented more information, but the question was, could this information be used with today's laser systems to provide better refractive solutions?

Some of the comments:

On the subject of wavefront versus topography:
  -- topography may be valuable for planning ablation
  -- gather the topography, but treat with the wavefront
  -- wavefront doesn't give the location of the aberration,
     need the topography to  find out where it is
  -- topography is probably quite good, but wavefront is
     the future and will be done.

Can wavefront be used to create new contact lenses to compensate for higher
 order aberrations?
  -- possibly, but topographic analysis is good too
  -- could make a wavefront CL, but it would ride/move on the corneal surface
  -- easy to make the CL (both VISX and Asclepion are making trial lenses)
     but the  problem is keeping it centered on the eye

What about Hartman Schack aberrometers versus Tschenring?
  -- clinical evidence isn't in yet
  -- no comparative data yet, as to which provides better information
  -- HS has been used for gathering astronomical data with excellent results.

And, some of the more creative panel members gave thought to the possible use of wavefront in the future for tracking cataract formation and diagnosing dry eye and other systemic problems of the visual system.

All in all a very interesting and productive two days of discussion about the future of customized refractive surgery.

Customized Ablations #3: Getting Closer Yet

This is the third of a series of eight articles chronicling the development of Customized Ablation or Wavefront Directed Lasik. This column was written following the Spring 2000 ASCRS meeting and was published in the August 1, 2000 issue of Ocular Surgery News.

Customized Ablations: Getting Closer Yet

Technology Update
Irving J. Arons
Spectrum Consulting

Since I first heard about the possibility of enhancing vision via customized ablation from Marguerite Mcdonald's presentation at the 1998 AAO meeting, I have been intrigued with the concept. This interest was reinforced by a presentation given by Tim Turner, director of research at Orbtek, at the Spring 1999 ASLMS meeting, and by a tape of a course given at the 1999 ASCRS by the Autonomous Team, as I wrote in my column in the June 15, 1999 issue of Ocular Surgery News, "I've seen the future...and its CustomCornea".

Then, following last year's AAO meeting, I became convinced that the idea was viable and close at hand as I wrote in my column in the February 15, 2000 issue of OSN, "Customized ablations: the future is close". Now, following this Spring's ASCRS meeting, I have heard first hand of the early results on the initial human clinical trials and am convinced that custom ablation systems from several manufacturers will be coming to the market, perhaps as soon as the end of next year.

In an attempt to put this into perspective, I have interviewed all of the companies involved and have written descriptions of their programs as well as a side-by-side comparison of the specifications of their current laser systems in the accompanying table.

Before beginning, however, I should warn you that there are many problems yet to be resolved before routine customized ablations become the norm. Many questions remain to be answered:

● At what limiting age, considering the potential for cataract formation and the onset of presbyopia, should customized ablations not be considered?

● Should all higher order aberrations be corrected for? Can this be adequately done on the sub-surface of the cornea? What effective correction is achieved when performing customized LASIK on a patient following wavefront analysis, and then placing the flap back on top? Perhaps customized ablations ought to be done in two steps; perform LASIK with today's lasers, allow the cornea to stabilize, and then retreat/enhance to reduce some higher order aberrations for the best results. (What about the effect on correction of the smoothness of the microkeratome?)

● Can laser technology ablation-precision catch up with the precision of the diagnostic techniques? (LASIK done with wide-area ablation lasers increases higher order aberrations from 5-15 times, although the same procedure done using a small spot scanning laser employing an eye tracker can reduce the increase in aberrations to only 2-3 times that of the untreated eye. As one analyst has suggested, is wavefront sensing followed by LASIK an exercise in futility?)

● What about floaters? Will they show up on wavefront analysis, and since they move, how do you correct for them?

● What is the effect of the tear film?

● As Jack Holloday has espoused, what about corneal shape? Can most of the visual acuity be accounted for by just retaining the cornea's prolate shape, rather than making it oblate, as is done by most ablations today? (Should customized ablations be made to retain the corneas' asphericity?)

● And an even bigger question -- do most people really want to see 20/15, 20/10 or 20/8? Isn't 20/20 good enough? After all, this can be achieved routinely today. (Recall the story of the woman treated by Theo Seiler to 20/8 who couldn't watch television clearly, seeing only the raster lines!)

Assuming that all of the above questions -- and others that I haven't thought of -- can be eventually resolved, here is a company by company update of what each is doing to advance the state-of-the-art towards customized ablations.

Asclepion-Meditec

Asclepion-Meditec, one of the pioneers in refractive laser surgery, who introduced their first excimer laser for medical applications in 1986, offers the new MEL 70 G-Scan, small spot scanning laser, incorporating a contrast-stabilized video active eye tracking system, that is capable of supporting either topographic or wavefront analyzed patients. The topographic supported customized ablation (TOSCA) system, operating for more than two years on more that 50 work stations installed worldwide, has been utilized in treating several hundred eyes with excellent results. Wavefront aberrometer supported corneal ablations (WASCA) is new this year, with a prototype Hartmann-Shack wavefront analyzer under evaluation, and about 30 eyes treated, with 3 months followup to date.

In addition to the above, new innovations from Asclepion this year include a cone for controlled atmosphere (CCA), to remove smoke and debris from the ablation field without causing dehydration of the corneal surface, and its tissue saving algorithm (TSA), used in conjunction with the TOSCA approach to remove up to 70% less corneal tissue.

Bausch & Lomb

B&L has launched Zyoptix, its new system for Personalized Vision Solutions, which incorporates its ZyWave Hartmann-Shack aberrometer coupled with its Orbscan IIZ multidimensional 3D corneal measurement device. This gives an integrated diagnostic for use with its Technolas 217Z Zylink software.

The laser uses a combined 2 diameter flying spot approach. First, a 2 mm spot is used to correct most of the refractive error, then the spot size is reduced to 1 mm to correct the fine structures, such as higher order aberrations. This, combined with a truncated gaussian beam, results in maximum smoothness of the corneal bed, minimal thermal effects, less tissue removal and a wider optical zone in an efficient treatment time. The company's laser also incorporates an active 120 Hz eye tracker.

LaserSight

LaserSight has taken a dual approach to customized ablations, introducing its line of Astra products. The company has developed both a topographical link to its LaserScan LSX laser, ASTRA (Advanced Shape Technology Refractive Algorithms), using corneal interactive programmed topographic ablation (CIPTA), for both irregular and regular corneal surfaces, with several thousand patients treated to date; but also, via the acquisition of diagnostic intellectual property from Premier Laser Systems earlier this year, will shortly have the capability to provide an integrated refractive diagnostic work station that includes front-to-back analysis of aberrations within the total eye. The CustomEyes system includes ASTRATrack, an eye tracking system designed to meet demands for performing the CustomEyes procedure; ASTRAPro, the software for planning the CustomEyes treatments; and ASTRAMax, the integrated ophthalmic diagnostic workstation that provides the data required to plan the CustomEyes treatment. The latter device uses a Hartmann Shack spatially resolved refraction system, that will be combined with 3D pachymetry, scotopic pupillometry and posterior corneal topography, to give an accurate measurement of total eye aberrations along with corneal shape and curvature.

LaserSight expects to complete its international trials and launch the topographic product in the international market during the third quarter of this year. U.S. clinical trials for the ASTRA technique are anticipated to be completed by year end with a U.S. commercial launch expected some time next year. The ASTRAMax refractive wavefront diagnostic should be ready for evaluation later this summer. Upon completion of development, the new work station will integrate wavefront analysis and corneal topography into a single instrument with additional diagnostic capabilities. ASTRA CustomEyes represents a new standard of eyecare that goes beyond conventional laser vision correction by individualizing the laser treatment utilizing a patient-specific set of diagnostic criteria intended to address and control both refractive error and optical aberrations.

The advanced diagnostic workstation will be employed with LaserSight's small spot scanning LaserScan LSX high-speed laser (100 Hz currently in the U.S., but 200 Hz internationally), along with the company's active video tracker (ASTRATrack) for stabilizing the eye.

Nidek

Nidek has taken a different approach to customized ablation. First, the company has adapted its EC-5000 laser system to produce both a scanning slit for accomplishing most of the ablation, followed by converting the slit aperture to a segmented spot scan, using from one to six spots along the length of the slit, to complete the ablation -- somewhat similar to VISX's variable spot size laser, which uses its wide area aperture for about 80-85% of the ablation, followed by a small spot for "polishing" and customizing the correction. Since the six spot aperture has a spatial filter, the energy output of each spot is quasi-gaussian. The laser also employs an active video tracker with automatic centering, but which can be de-centered by the operator.

For the diagnostic input, Nidek uses a "souped-up" autorefracter, formerly known as the ARK 10,000, but now called the OPD-Scan (optimal path difference). It uses a slit lamp bundle of light that scans the retina (1440 measurements), a form of retinoscopy, with the reflected light signal picked up by photodetectors. In addition, the device employs topography to take accurate surface measurements which are combined with the retinoscopy to give refractive error through the whole pupillary area of the cornea, along with corneal shape. This information is fed into Final Fit software in a PC which calculates the ablation data needed for performing the customized ablation by the laser.

Currently, the ablation diagnostic data input is fed to the laser by means of a floppy disc, but eventually this could be done directly.

Schwind

Schwind introduced its new sixth generation scanning small spot laser, ESIRIS, at the ASCRS meeting. This 1 mm spot beam, 200 Hz repetition rate laser, has been combined with an ultra-fast 300 Hz acquisition rate eye tracker and ergonomic design for an attractive package for performing LASIK and customized ablations. In addition, the company has developed ORK-link (Optimized Refractive Keratectomy), which connects either to a topographic system (Technomed C-Scan), or to its new Schwind Wavefront Aberrometer device for measuring optical aberrations. The latter is based on the Tscherning wavefront sensor developed by Theo Seiler and his team at Dresden University. To date, more than 120 patients have been treated with the system, and more than 1000 patients are expected to be treated by September of this year.

Based on 3-month followup results obtained on the first 30 eyes treated with the system by Prof. Seiler, 60% obtained 20/16 or better (10% achieving 20/10); and an additional 30% achieved 20/20. Thus, 90% of the eyes treated achieved 20/20 or better, compared to a side-by-side test of LASIK, where 85% were 20/20 or better, but only 35% were 20/16 or better.

Summit Autonomous

Summit, one of the leaders in the wavefront customized ablation race, displayed its new LadarVision 4000 system, employing a 4000 Hz acquisition rate tracking system for stabilizing eye movement during ablation and built-in software for hinge protection during LASIK.

The major differences between the LadarVision system and its competition, is that the laser operates at the lower end of the repetition rate spectrum (60 Hz -- with only Asclepion-Meditec at 35-50 Hz and VISX at 10 Hz slower), while the company's tracker is at the high end (at 4000 Hz). Also, currently, wavefront measurements are taken on a dilated eye so that the company can deal with the type of aberrations that patients have to deal with during night driving. Research is underway to also evaluate undilated eyes, and to deal with both accommodated and unaccommodated states.

The first U.S. customized ablation was performed last October by Dr. Marguerite McDonald, using the Summit Autonomous CustomCornea analyzer and LadarVision system. Since then -- and through the ASCRS meeting -- about 35 patients have been treated (one eye with customized ablation and the other with either PRK or LASIK). Expanded U.S. clinical trials are currently underway. Early results from these trials indicate that some patients can achieve 20/12 vision, while others are getting 20/16. The company expects to complete its clinical trials and gain marketing approval for the system by the end of next year.

The wavefront device, which was demonstrated during ASCRS, takes five scans of the eye in a very short time, and selects the closest matching three scans for data input into the laser. The device, being built by Summit Autonomous' partner, Zeiss Humphrey, has been approved for marketing by the FDA and will be commercialized this fall.

VISX

VISX, like Nidek, has taken an interesting approach to customized ablations. The company's new Star S3 laser system employs "variable spot scanning", wherein the bulk of the refractive ablation will be done with its SmoothScan wide area ablation system, and final customized "polishing" will be done by a small spot scanning beam, ranging in size from 0.65 to 0.8 mm. Although the VISX SmoothScan is the slowest of all of the laser systems, operating at only 10 Hz -- with an upgrade to 20 Hz expected shortly, because it uses the full wide area beam for most of the ablation, total ablation time is equivalent to that of other systems (see the accompanying table). This technique also results in less ablation of tissue.

VISX has also added an active 3D infrared video eye tracking system to the Star S3 system, that tracks in the x and y as well as in the z axis, tracking the movement of the natural pupil.
The company's WaveScan Wavefront measuring system, developed by 20/10 Perfect Vision, is the only one with a patient feedback loop that provides the subject with an eyechart showing vision before and what it might be after customized treatment. The device, approved for marketing by the FDA, is expected to sell for about $75,000 and be available by the end of the year. Early results on 10 patients after 1 month, showed that 80% of WaveScan evaluated eyes had uncorrected vision of 20/15, compared to 60% of those treated based on manifest refractions.

The company expects to roll out the Star S3 laser by year's end, selling for $425,000, while current Star S2 users can obtain upgrades/conversions for $100,000. New laser purchasers can order Star S2s, which will include the upgrade and WaveScan (when available) for $425,000.

WaveLight

As previously written, the WaveLight Allegretto laser system is at the forefront of customized ablation, having been the first system used by Prof. Theo Seiler nearly a year ago (July 1999) in testing his Dresden Wavefront Analyzer. The Allegretto is small spot scanning system that operates at 200 Hz and has a 250 Hz active tracking system based on an infrared camera. This pupil-based tracker uses a patented illumination system to guarantee stable tracking throughout surgery, and is auto-centering, or can be decentered by the user.

An FDA clinical trial is currently underway in the United States for correcting myopia with LASIK. This trial will be expanded to include customized ablations, using a wavefront device based on the Dresden Analyzer, sometime in the near future. In European customized ablation trials, more than 60 patients have been treated with excellent results.

In late-breaking news, WaveLight and Coherent Medical have announced that Coherent will be WaveLight's exclusive marketing partner in Europe, Asia, and Latin America. No announcement has yet been made for the United States.