Algorithms, Allegretto and Accounting

Round Table

The best postoperative regimen for refractive surgery patients

Ronald R. Krueger, MD, MSE, Moderator

Dr Krueger: We have an initial panel, and we wanted just to address some things that bring us back to our basic practice in LASIK. What are some of the postoperative management regimens in terms of drops and techniques, and things that various people here on the panel would use, and we would also like to keep it open for some questions as we go along. I just have a series of different questions and slides. We will go through them individually, and will then have some discussion, and then move on to the next talk. Number one is what is your preoperative pharmacological regimen for LASIK and why? I noted down things like, what are your anesthetic drops, artificial tears, what do you put on your cornea just as you are about to make the pass with the microkeratome? Things like that. Karl, since you are first, why don’t you tell me a little bit of yours.

Karl G. Stonecipher, MD: Simply put, I obviously do my anesthetic in surgery. I just use a topical proparacaine, just generic. I don’t use artificial tears before surgery, like you suggested, but I think that is a great idea. There were several studies out there that Celluvisc was causing problems in terms of DLK, and so I now put a half-and-half mixture of Refresh Tears in the bottle with Celluvisc and I don’t see the DLK, but if you just use straight Celluvisc, and I use that right before the pass, I basically just put one vial of Celluvisc in one of those little bottles and we use that intraoperatively.

Dr Krueger: Herb, why don’t you give us an answer too.

HerbertKaufman,MD:I just use anesthetic. I think it’s worth mentioning that BSS usually rots your microkeratomes, so that ought to be used with very great caution.

Steven Schallhorn, MD: The proparacaine is all I use preop. In a case where I want to mark the cornea, I obviously put proparacaine in before marking the eye, and if the eye needs dilation obviously that would go in preop, but proparacaine is basically the only drop I use, and I lubricate.

Dr Krueger: And how soon before you are doing the procedure do you actually put in your proparacaine?

Dr Schallhorn: We prep the patient, and so it is normally within a minute or two. Try to absolutely minimize that.

Wavefront and Emerging Refractive Technologies, pp. 117–125

Proceedings of the 51st Annual Symposium of the New Orleans Academy of Ophthalmology, New Orleans, LA, USA, February 22-24, 2002

edited by Jill B. Koury

© 2003 Kugler Publications, The Hague, The Netherlands

Dr Krueger: So they are already in the laser room?

Dr Schallhorn: Yes, they are on the table, unless I am marking them first. The other thing is we do a lot of PRK, and that’s exactly the opposite of the PRK regimen, where loosening the epithelium is good. Not LASEK but straight PRK is a good thing, and so the techs really have to change mind sets, especially if we are doing PRK and LASIK in the same day. We minimize the time. I want the absolute minimum amount of time between proparacaine and the procedure so that the epithelium doesn’t loosen, whereas it is just the opposite for PRK.

Marc Michelson, MD: Before I answer this question, what was your comment about balanced salt solution?

Dr Kaufman: Balanced salt will cause rust in the microkeratomes.

Dr Michelson: We use the Ladar Vision System, so I always mark the patient, and so the patients are getting a drop of anesthetic plus their dilating drops a good 15 or 10 minutes before surgery. A lot of times when I go in to mark the patient, I notice that the epithelium may already look a little ratty, so I have the patients keep their eyes closed, and I notice just with a few seconds of lid closure that the epithelium may look better. So I like to make sure that the patients are not sitting there with their eyes open and just keeping their lids closed. When the patients actually come into surgery, I make this one comment, we do not use Acular, as has been suggested. I noticed that the minute we used Acular we had slipped caps, so I stopped using Acular. We use one drop of the proparacaine and then one drop of 4% lidocaine, and then I profusely irrigate the eye with a copious amount of BSS. I want to get the oils off the tear film. I don’t want to be making a translation of a microkeratome with any of the debris in the tear film, so I copiously irrigate and when I am satisfied with that I proceed with the case. Immediately afterwards, we use an antibiotic of choice, it doesn’t really matter.

Charles Moore, MD: The one thing that I do differently pre with the drops – I use proparacaine exclusively, one drop as we start, and then we irrigate with proparacaine as we run the keratome across. We have learned to put the proparacaine bottles in ice and chill them down, and the cold definitely cuts down on epithelial problems.

Dr Krueger: Since I use Ladar Vision, I dilate the patients about 20 minutes in advance of them coming into the room, and then just prior to coming into the room I put in the first drop of proparacaine, mark the 3 and 9 o’clock axes so I can make sure there is no cyclotorsion, and bring them right into the room and just go ahead and give them one more drop before they get started.

Dr Schallhorn: Ron, how do you mark?

Dr Krueger: I use a gentian violet pen. I have them sit with their forehead up against the slit lamp, make sure that everything is straight, and I mark 3 and 9 o’clock, having put the slit lamp light all the way to the side so you can get a nice light showing you where 3 and 9 are. I press several times. I press it, and press it, and press it, and as long as I don’t get a tear film welling up on my pen, I actually get a very deep mark there that will last for half an hour or so. So you can easily see it during the case as well.

Dr Schallhorn: That’s exactly the technique I use, pushing firmly with that pen.

Dr Krueger: Push, then I take it off and push again and kind of dab it, and that really makes sure the ink stays in so you can get something that lasts.

Next question: How long do you keep patients out of contact lenses before evaluation, and that is either soft or RGP lenses? Then what criteria would you also use for ruling out a subclinical keratoconus case?

Dr Moore: That’s a great question. It seems like the longer we keep the contact lenses out, the more we learn. These people that have been wearing contact lenses for 20 or 30 years, and particularly those patients who have been sleeping in the extended wear lenses, I have found seven days is an inordinately small amount of time and usually not adequate. So frequently, for these people, we will wait for a month of no contact lenses.

Dr Krueger: That is soft lenses?

Dr Moore: Even soft, yes, extended wear. As long as we are still seeing any keratometric or topographic changes, and we don’t have good stable reproducibility, we won’t do the case.

Dr Krueger: And what kind of criteria for subclinical keratoconus?

Dr Moore: I like the OrbScan testing for the subclinical keratoconus because it is so accurate in picking it up and doing pachymetry for you.

Dr Michelson: Regarding the keratoconus, we are looking for a 3 D or more change between inferior and superior.

Dr Krueger: Within the central 3 mm?

Dr Michelson: Within the central 3 mm. Soft lenses routinely five to seven days absent keratometric changes. Contact lenses that are hard or rigid, we like to wait a minimum of two weeks. However, with the presence of keratometric changes, we will sometimes wait up to six to eight months, and that usually pays off because in a patient who has an abnormal cornea on topography, waiting that length of time, that investment will produce a 20/20-20/15 eye.

Dr Schallhorn: The soft contacts is normally about five days. The gas perms, we have a program where we get them out of their lenses immediately, and we normally want to see them within several days of being out of their contact lenses, and we do topo’s and refract them. Then we have a program where really every two weeks they come in and get keratometry, get a manifest refraction and a visual acuity. We do that at least twice. So they are out at least a month. But as you were saying, it could be many, many months, and it is interesting to track the changes. We actually have a program to do that with gas perms. I think it is very, very important. As far as the criteria are concerned, we use sort of a modified Rabinowitz where we look at inferior-superior values. We take I think it was five points superior and five points inferior, 3 mm though. And then

if the difference of the average between superior and inferior is more than 3, that is sort of a rough criteria. I also like to look at how well they are correctable, what their bestcorrected visual acuity is, what their amount of astigmatism is and their manifest refraction, and how stable they have been. So, if it has been even less than that, if I don’t have kind of a warm and fuzzy feeling with those other clinical parameters, we would exclude them based on that.

Dr Krueger: So you’re still saying 3 D between superior and inferior, and does it matter at all whether they are 47 on the higher or 44 on the higher?

Dr Schallhorn: Yes, if they are steep right off the bat, that’s a warning sign. Anyone who is more than 47, we generally would exclude them, period. So that’s another point.

Dr Krueger: Even if they are very symmetric?

Dr Schallhorn: Yes, even if they are symmetric.

Dr Kaufman: What Steve Schallhorn does is better than what I do, because some patients will change slowly over time after hard lenses, and it may take up to months. Rule of thumb, a minimum of one week, preferably two weeks off for soft lenses, and three weeks for hard lenses, knowing that if I do that I will still have some patients who probably are not stabilized. For a topography for keratoconus, I use Steve Klyce’s criteria with the understanding that there are occasional cones you will still do. But I sit down and reason with the patient and worry a lot about that.

Dr Stonecipher: For me and contact lenses, it is a week for soft, two weeks for soft to work, and it’s about a month per decade for wear for the hard lenses. I recheck everyone the day of, as you have heard me harp about, and see if they have any changes, whether they are topographic or contact lens related. And the other issue is pachymetry related. Sometimes you will get people who have normal pachymetries and have worn contact lenses they have slept in and they take them out and their corneas will actually get thinner and go below what you feel comfortable in treating with LASIK. As far as keratoconus goes, I always remember the story that Marguerite told me of the patient who shows up in her clinic and she says, “Sir, I have to tell you this. You have this problem called keratoconus”. And the patient looks back at her and says, “I was hoping that you wouldn’t find that”. So obviously they have been somewhere before and have been told that they have problems, and you are going to find that more and more these days. My Humphrey is probably over-sensitive, but I would much rather be a little over-sensitive, and I also have access to an EyeSys and an OrbScan, but more importantly for me lately, and, again, I am not a financial advisor to these guys: the Confoscan. When in doubt, and you are probably finding these popping up more and more, if you have someone who either has an asymmetric bow-tie or they are on the thin side or whatever, the confocal microscope picks up a lot of these patients who normally I may have done five years ago and who I’m not doing today.

Dr Krueger: I pretty much look at an absolute minimum of three days for soft lenses, but I have to look at the topo’s to see what they look like, and if they are abnormal it is going to be longer. And three weeks with the rigid. Again, if it looks abnormal, I am

going to tell them, “Guess what, there is still warpage going on, you need to take another month or more and then we will have to check it again and see if it’s better”.

Dr Moore: Ron, one other thing. In going through my refractive surgery consultant outcome analysis for Wavelight, I was astounded to find that 90% of my patients were contact lens wearers and only 10% were spectacle. I think what has happened is that all these contact lens people who are having problems with their contacts perhaps form fruste and other things, and they are coming in to get LASIK because they are having problems with their contacts, and we really have to be aware of that.

Dr Krueger: And a lot of them are the ones that have dry eyes with their contact lenses and then they come in and want LASIK done. Again, I pretty much look at the Humphrey as well, just to see if there is some significant steepening. I use that with keeping out the contact lenses to see if that helps. What is your intraoperative pharmacological regimen for LASIK and why use things like antibiotics, steroids, nonsteroidals, tears, other things? Karl, let’s start with you.

Dr Stonecipher: Number one, I have started the infectious realm along with my dry eye research and have looked at 755 corneal ulcers and 1029 eyelid cultures, and bacterial conjunctivitis, both as a resident and as a fellow, and I got a pretty good grip on the fact that you don’t want any of that in your refractive patient population and, knock on wood somewhere, I don’t own an infection after over some 20,000 odd cases, and I think that part of this is because of the regimens we look at, and they should always be changing. Right now, I am using Pred Forte and Ocuflox. If I have a health care worker, someone who I think is exposed to more virulent pathogens, I may add an aminoglycoside, but as we are looking at our fluoroquinolones starting to run into problems in terms of resistance, if I look back at my Ciloxan data on these corneal ulcers, we were starting to get some resistance to it, and now you are seeing that pop up with Ocuflox. Well, Quixin hasn’t been out there long enough, so I wouldn’t be surprised if more and more people started using it as their postoperative regimen just solely because of the fact that it is going to cover more things at the present time. Now you talk about penetration and all that sort of stuff, and I am not going to get into that, but one thing I know is that a lot of people are still using tobramycin, and I just don’t think that is adequate coverage. Personally, I feel uncomfortable leaving them on that. I may change one of my things after talking to Marc today. Probably one of my most problematic things is a slipped flap. That’s my number one complication. I was talking to Marc, who said this about Acular, and I do use Acular intraoperatively because they don’t have as much pain. I was part of the FDA trial for Voltaren, and people were dying downstairs who didn’t get Voltaren with PRK and who were willing to pay for it. But I may start changing that and letting the guys burn a little bit more postoperatively and try to see what happens.

Dr Kaufman: There are pretty good data that the best way to sterilize an eye that has not been exposed to anything before is to use Povidone iodine as part of the prep. And so I think that everyone should probably get Povidone iodine before they do the procedure. I’ll bet that most of us agree to that. As far as what to do at the time of surgery, thereafter, again, I think a fluoroquinolone, and probably there is less resistance to Quixin now than to the other fluoroquinolones, and I wouldn’t use an aminoglycoside, and I don’t use NSAIDs either.

Dr Schallhorn: As far as medications are concerned, Ciloxan and Pred Forte.

Dr Michelson: The drugs are the drugs. I am going to talk about something else. When I went to learn how to do ALK with Karl Stonecipher in 19-whatever, I learned how to do ALK gloveless because of the debris, so I just naturally morphed into doing LASIK gloveless. I went through a very, very stringent sterilization process of myself, my hands, a strong scrub, and an alcohol based scrub following that, and I have just started using powderless gloves. But I have gone through lamellar procedures since 1994 without a single incidence of an infection. And we change our antibiotics. A drug rep will come in one day and you will change. I’m not sure how critical that is. I just want to mention the fact that I don’t use gloves and haven’t used gloves for many, many years, but I scrub my hands on every case. We use sterile techniques and I use an alcohol base foam after a scrub, even between eyes. I will go back and re-foam. So I think that’s critical also. I don’t know how many people use gloves or don’t use gloves in LASIK, but now that powderless gloves are available, I think, to protect myself, I need to use gloves.

DrStonecipher: That’s a good question. How many people don’t wear gloves in LASIK? I wear gloves, but how many people don’t wear gloves. It is still a pretty healthy number.

Dr Krueger: I was in a laser center and there was another surgeon there operating right before me and one of the first patients I treated was sitting there watching, and he was totally aghast that the surgeon before me was not using gloves. He kind of brought it to my attention, he kept repeating it, so I think your patients are aware of that and they might be concerned if you are not. Charlie, real quick, we are going to try to keep these to single-word answers or to real quick answers.

Dr Moore: Quixin, Pred Forte, Tears, Dura Tears, until they come out of your ears.

Dr Krueger: I use Flarex and Ciloxan. I do use one drop of Voltaren right at the time of surgery and that’s it, never postop, and lots of tears just before. What is your postop pharmacological regimen for LASIK and why and for how long? Same sort of questions. We will start with Charlie. The same drugs?

Dr Moore: Same drugs.

Dr Krueger: And how long do you use them?

Dr Moore: Quixin five days, the Pred Forte anywhere from one to seven, depending on the patient, and tears for up to three months if I can get them to use them.

Dr Michelson: Ditto.

Dr Schallhorn: Pred Forte and Ciloxan four times a day for five days and then tears often and for months.

Dr Kaufman: The same.

Dr Stonecipher: Mine is a little different. I do Pred Forte and Ocuflox still, but I tell them to take it for two weeks because I figure, with our patient population in North Carolina, that means I am going to get about five days out of them, and that is usually what happens.

Dr Krueger: And I do it for about a week four times a day, just have them stop, and have them use lots of tears to continue. A little different direction with LASIK. What are your criteria for selecting LASEK or PRK over LASIK in your patients, and what percentage of LASEK would you say you are doing, and you can see some of the lists of different reasons for considering doing LASEK? What would you say Karl?

Dr Stonecipher: LASEK, I’m probably doing less than one percent. It’s people who have thin corneas. I have tried to do LASEK on a couple of map dot fingerprint dystrophy patients, and it took them forever to see well afterwards, so I am just still going back and doing typical PRK in most of them.

DrKaufman:Thin corneas and some very low refractions, I do LASEK, all the rest LASIK. Not dot fingerprint. I think it’s treated with PRK, that’s the treatment of choice.

Dr Schallhorn: I haven’t done any LASEK yet. We still do a lot of PRK. And those five things you have listed are the indications. The one other PRK population we do is anyone who is in a job where they can’t have LASIK, and that would primarily be aviators in the military who can’t have it. So what percentage of PRK versus LASIK: last year 2500 total procedures, 1500 LASIK and 1000 PRKs.

Dr Michelson: I would just add one other criterium to that. All our post-penetrating keratoplasties are surface ablation. I do not like doing lamellar procedures on graft patients.

Dr Moore: I would say ditto. The only avocation besides what you mentioned would be a boxer, and I have done a couple of those.

Dr Stonecipher: Steve, since you brought it up, will you make a comment for all of us out there in terms of military rules these days, because the Navy kind of has a don’t ask, don’t tell policy, and if their superior officer says it’s okay, it’s okay, but then the Seals guys, they have to have PRK. What is out there now?

Dr Schallhorn: If someone is on active duty, they can have either PRK or LASIK if they get their commanding officer’s approval, in other words, their boss. Their boss has to approve it because of the time off and that kind of thing. With two exceptions: divers and aviators cannot have LASIK. The reason for this is still concerns about the flap, environmental issues relating to the flap, and these are jobs that are high asset, high cost jobs, and the necessity to check every block and make sure that everything is square, make sure we understand all the environmental issues with LASIK. Basically, for them it’s approved if they get their CO’s approval. There are thousands who have had it. People who want to get into the military, want to get in the Navy, all forms of refractive surgery are disqualifying, but there is what we call a uniform waiver criterium for entry into the military. That uniform waiver criterium is really a way to specify parameters that the patients have to go through either before or after. For instance, they

have to have less than 8 D of ametropia, and that is so you can have an ametrope who wants to enter, but if they are a –20.00 myope before surgery, we know that that eye is not the same as a naturally ametropic eye. There are other restrictions related to that, but basically if you have a low myope who has done well from either PRK or LASIK, they can easily enter the service, and thousands have, but no LASIK in people who want to go into aviation. PRK is okay. Actually, there are over 100 people right now in flight training to be a Navy pilot who, prior to this program, would not have qualified to be Navy pilots, but because they have had PRK and they have been accepted into this program. So there are some certain specific requirements related to that. But they can have PRK and become Navy pilots.

Dr Kaufman: I’ve done some LASEK and my patients have pain, and I don’t know if it’s me or something I’m doing. I’d like others to comment on whether LASEK really gets rid of the pain, in your experience.

Dr Krueger: You are saying that you are having pain in your LASEK?

Dr Kaufman: Yes, postop pain. Yes, LASEK.

Dr Krueger: I still have pain in a number of patients, but every once in a while, when everything goes smoothly, they come back and say that they felt nothing and that they were comfortable. So it is still unpredictable for me. What intraoperative steps, techniques do you apply in your LASEK cases? In other words, alcohol percentage, how long do you hold the alcohol in place, do you use a well of alcohol or put a sponge of alcohol on, what do you do to score the epithelium, what kind of instruments might you use, and do you have any unique steps? And also, does anybody use mitomycin with LASEK for the higher corrections?

Dr Stonecipher: With my LASEK technique, I was initially using alcohol for longer times upwards of around a minute to a minute and a half, and my patients were coming back and not seeing well, and it took a while for them to see well. I think that Steve Wilson and Steve Klyce and a lot of these people were talking about apoptosis with that, and that is a real issue, so we are down to 20-30 second times with the alcohol. I use just a standard LASEK and I don’t even know who gave it to me, but I just bought one of the kits and started using it. I like it, but I’m not enthralled with it. In some of my postops, I haven’t yet seen a huge difference in how much better they perform than my PRK patients, but that may just be a learning curve.

Dr Krueger: It’s about 20% alcohol, I probably go about 30 seconds, and I score the epithelium with a trephine a little bit. I’m sure Dan will talk a bit more about that when he gives his talk later as well. And finally: what is your post-op regimen with LASEK? When do you take off the contact lens, probably somewhat similar. Does anybody use steroids longer, because it’s like a PRK type of procedure? Do you use it for a week and stop steroids?

Dr Stonecipher: For LASEK, I do exactly the same thing.

Dr Krueger: I actually go longer. I will go for about two months or more with the steroid, take the contact lens off at least about four days or so afterward. Finally, what is your

cut off for performing a corneal refractive procedure versus a lens extraction or nothing with regard to the age of the patient, amount of sclerosis you might see in the lens, visual acuity, best-corrected visual acuity, level of myopia, hyperopia?

Dr Stonecipher: The cut-off criteria for clear lensectomies for many people are 50, especially in the hyperopic population, not so much in the myopic. I started doing clear lensectomies back in 1992, 1991, and presented a bunch of data and looked at that, and in my hyperopic population, I have done fine. In my myopic population, I always had them checked by my retina surgeons preoperatively, and they have really done well. I have only had one patient who developed a subretinal neovascular membrane and lacquer crack. He was a –26.00 and that was like nine months postoperatively, so I think it was unrelated to his clear lens, but I think there are a lot of people out there who are pushing the Prelex. I think that is fine, but with the hyperopic ability to treat people now, you are seeing a lot of older patients who are coming in for hyperopic and hyperopic astigmatic treatments. I think you have to let them make the decision. I usually give them both LASIK consents and clear lensectomy consents, and then let them make the decision.

Dr Kaufman: In young people, I like phakic IOLs. I think they are wonderful. I am a wimp and I don’t do clear lens extraction. On the other hand, it doesn’t take much of a cataract in someone who really has a significant refractive change to make me do it earlier.

Dr Krueger: If you had someone who was 20/25 best-corrected with some sclerosis changes, would that be enough to say you would do a cataract extraction?

Dr Kaufman: If in the glare they go down to, say, 20/40.

Dr Krueger: So you BAT them down with glare, sure. OK, that’s all for now. Thank you panel for your comments.

LASIK results with the WaveLight Allegretto Wave Excimer Laser System 127

Interim (three-month) LASIK results with the WaveLight Allegretto Wave Excimer Laser System

Guy M. Kezirian1 and Karl G. Stonecipher2

1SurgiVision® Consultants, Inc., Paradise Valley, AZ; 2Southeastern Laser and Refractive Center, Greensboro, NC; USA

Abstract

Purpose: The interim (three-month) results of a US Food and Drug Administration (FDA) Investigational Device Exemption (IDE) trial of the WaveLight Allegretto Wave Excimer Laser System for the LASIK treatments of spherical and spherocylindrical myopia are presented. Methods: The study is being conducted at 11 sites in the USA, using a protocol that follows the published FDA guidance for excimer laser studies. The results are evaluated against prospectively defined targets for safety and effectiveness. Results: The outcomes of 751/808 (93%) eyes of 418 subjects enrolled at 11 sites from February through September 15th, 2001, are included in this report. There are 241/751 (48%) sphere and 510/751 (52%) spherocylinder treatments, ranging up to –12 D sphere and –6 D cylinder. An uncorrected visual acuity (UCVA) of 20/16 or better was achieved in 59.3% eyes targeted for distance vision. UCVA 20/20 or better was achieved in 86.2% of eyes (target 50%). The ± 0.50 D rate was 649/750 (86.5%) for all eyes (target 50%). On average, eyes gained 0.70 lines (standard deviation (SD), 0.87 lines) of best spectacle-corrected visual acuity (BSCVA), with a loss of two or more lines occurring in 3/750 (0.4%) eyes (target < 5%). Discussion: Each of the protocol targets was easily exceeded, and the results compared favorably with similar regulatory studies submitted for other lasers. Further follow-up is needed to evaluate refractive stability, patient subjective results, and other protocol targets.

Introduction

The WaveLight Allegretto Wave Excimer Laser System (WaveLight Laser Technologies, AG, Erlangen, Germany) is a flying-spot excimer laser used in refractive surgery. The laser utilizes a 0.95 mm gaussian-shaped beam with a 200-Hz repetition rate.

Excimer lasers are currently classified as Class III (‘substantial risk’) medical devices, which are required to obtain regulatory approval from the US Food and Drug Administration (FDA) prior to commercial marketing and distribution in the USA. Clinical studies in support of applications for regulatory approval for Class III devices are conducted in formal Investigational Device Exemption (IDE) trials, which are subject to Institutional Review Board (IRB) oversight.

Address for correspondence: Guy M. Kezirian, MD, FACS, SurgiVision® Consultants, Inc., 4601 East Mockingbird Lane, Paradise Valley, AZ 85253, USA. e-mail: Guy1000@SurgiVision.biz

Wavefront and Emerging Refractive Technologies, pp. 127–141

Proceedings of the 51st Annual Symposium of the New Orleans Academy of Ophthalmology, New Orleans, LA, USA, February 22-24, 2002

edited by Jill B. Koury

© 2003 Kugler Publications, The Hague, The Netherlands

The IDE trials for regulatory approval for the Allegretto began in February 2000 in spherical and spherocylindrical myopic corrections with laser in situ keratomileusis (LASIK).1 The study sponsor is SurgiVision® Refractive Consultants, LLC of Paradise Valley, Arizona. Initial studies were conducted in 150 eyes, and then halted by the study sponsor, due to concerns about peripheral irregular astigmatism in some eyes. A new study, called Expansion A, was started in February 2001, after the laser was modified to increase the mean fluence to 200 mJ/ cm², add a plume evacuator, and other changes. Ablation depth per pulse is 40 µm.

This report details the three-month results of the 751 of 808 (93%) eyes which were enrolled in Expansion A through September 15th, 2001.

Patients and methods

Study design

The study is a prospective, multicenter, consecutive-enrollment clinical trial conducted under a protocol that matches the format recommended by the FDA.2 It was conducted under an IDE trial approved by the FDA. IRB oversight was provided by the Western IRB (Olympia, WA). Informed consent was obtained from all patients prior to entering the study, using an IRB-approved consent.

Patient population

The study is being conducted at 11 sites in the USA (Table 1). Patients enrolled from all sites through September 15th, 2001, in Expansion A, were included in this report.

Table 1. Listing of the 11 SurgiVision® Refractive Consultants, LLC Investigator Group contributing data to this report

LASIK results with the WaveLight Allegretto Wave Excimer Laser System 129

Table 2. Inclusion and exclusion criteria

Inclusion criteria

•subjects must be undergoing LASIK surgery for the correction of myopia

•intended treatment from 0 to -14 D of spherical equivalent myopia or myopia with astigmatism, with up to -14 D of spherical component and up to -6.0 D of astigmatic component. (All refractions measured at the spectacle plane.)

•subjects must have bilateral physiologic myopia

•BSCVA of 20/40 or better in each eye

•subjects must have had a stable refraction (0.5 D or less change in spheroequivalent) for the last 12 months, objectively documented (by previous clinical records, eyeglass prescriptions, etc.). Serial topographies will not be required

•subjects who are contact lens wearers must have hard or gas permeable lenses discontinued for three weeks and soft lenses discontinued for three days prior to the preoperative evaluation

•subjects must be at least 18 years of age

•corneal topography must be normal, as judged by the operating investigator

•subjects must sign a written informed consent form acknowledging their awareness of their participation in this study, the alternative treatments available, the risks involved, and the investigative nature of LASIK, and other issues that conform to the standard of care for informed consent practices

•subjects must be able to return for scheduled follow-up examinations for 12 months after surgery

Exclusion criteria

•subjects with anterior segment pathology

•subjects with residual, recurrent, or active ocular disease

•subjects who have undergone previous intraocular or corneal surgery involving the stroma in the eye to be operated on

•subjects who have a history of herpes keratitis

•subjects with diagnosed autoimmune disease, systemic connective tissue diseases or atopic syndrome, diabetes mellitus, or those taking systemic medications (i.e., corticosteroids or antimetabolites) likely to affect wound healing

•subjects with unstable central keratometry/topography readings with irregular topography patterns or keratometry mires, including signs of keratoconus

•subjects with known sensitivity to study medications

•subjects with an intraocular pressure of > 23 mmHg on Goldmann applanation tonometry, a history of glaucoma, or who are glaucoma suspects

•women who are pregnant or nursing, or who plan to become pregnant over the course of their participation in this investigation

•subjects who are participating in other ophthalmic clinical trials during this clinical investigation

•subjects with colobomas of the iris or other irregularities of the pupil margin

Population characteristics

Patients were enrolled according to the inclusion and exclusion criteria recommended in the October 1996 FDA guidance for Excimer Laser Studies,2 with minor modifications (Table 2). The criteria can be summarized as including patients with healthy eyes undergoing elective LASIK procedures for spherical or spherocylindrical myopia up to 14 D myopia and up to 6 D astigmatism, who are able to comply with the study follow-up requirements. Selection requirements specified predicted a residual corneal stromal thickness of 250 µm or more after ablation.

The surgical procedure

The LASIK procedure has been described elsewhere.1,3 In this series, keratome selection was left to the individual investigator. Keratomes used include the Automated Corneal Shaper (Bausch and Lomb, Inc., Rochester, NY), the Hansatome (Bausch and Lomb, Inc.), the Carriazo-Barraquer (Moria, Inc., distributed by Microtech, Inc., Doylestown, PA), and the Nidek Keratome (Tokyo, Japan).

In all eyes, surgery was planned to leave at least 250 µm of corneal thickness behind after ablation. Selected plate thickness was 160 µm when corneal thickness allowed; if not, a 130-µm plate was used.

All procedures were performed using the active tracker of the Allegretto laser. This tracker provides pulse-to-pulse tracking with a sampling rate of 250 Hz and a capture-to-shot-delivery (loop) time of approximately 6 msec. The tracker samples the edges of the non-dilated pupil and calculates a centroid based on the intersection of the X and Y diameters. All treatments were centered on the pupillary centroid.

Following creation of the keratectomy, the flap was reflected and laser ablation performed immediately. The use of irrigation fluid was kept to a minimum. Treatments were performed without interruption, unless the eye drifted out of the radial 2-mm range of the tracker, or unless visible moisture accumulated. Visible moisture was removed as needed using a stainless steel spatula.

All procedures were performed using the WaveLight Allegretto Wave Excimer Laser System (Allegretto) with a standard optical zone diameter of 6.5 mm; 6.0 mm was used to conserve corneal tissue when required. A blend zone of 0.6-1.4 mm was applied peripheral to the refractive treatment, depending on the treatment. Ablation duration was determined by the treatment amount, requiring less than five seconds per diopter. Beam calibration was performed at the start of each treatment day.

Spherocylinder treatments were performed sequentially, with the ablation for the sphere correction being carried out prior to the cylinder treatment. Cylinder treatments are performed using a ‘PTK’ method, whereby the cylinder is treated in one meridian while a PTK or refractively-neutral ablation is performed along the opposite meridian.

Nomogram adjustments were calculated early in the protocol using the overall results from all centers. This nomogram was incorporated into the laser software. Nomograms were calculated using the methods described by Holladay et al.,4 using the Refractive Surgery Consultant™ software program (Refractive Consulting Group,

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Inc., AZ). As specified in the protocol, nomogram adjustments only included refractive terms. No patient variables were incorporated.

Both eyes of patients undergoing bilateral procedures were operated on sequentially in same-day procedures.5 Retreatments for refractive improvement were permitted in the protocol after three months; however, this report is limited to single-procedure outcomes only. Results after retreatment are not included in this report.

Postoperative management

Postoperative medications included:

•topical antibiotic and/or steroid combination, four times a day for five days following surgery, then tapered or discontinued;

•topical wetting solutions, as needed;

•oral analgesics per the investigators’ discretion (optional);

•no topical non-steroidal anti-inflammatory agents (NSAIDS) were used after the first postoperative day.

Data acquisition and analysis

Surgical and clinical data were collected from clinical source documents and entered into the Refractive Surgery Consultant™ software program. Data were submitted electronically to the study sponsor. On-site audits for compliance with study standard operating procedures and for data integrity were conducted at each site.

For this report, eyes were analyzed as one cohort, except where otherwise specified. Results from the three-month postoperative interval, defined as ten to 14 weeks postoperatively, are reported here.

All calculations of visual acuity outcomes were performed using LogMAR equivalents.6 Refraction calculations were performed at the corneal plane, using vector analysis as appropriate.7 Refractive outcomes were reported compared to targeted amount.

Main outcome measures

Main outcome measures included distance uncorrected visual acuity (UCVA), manifest refractive spheroequivalent (MRSE), and change in BSCVA. Visual acuity measurements were made using an ETDRS chart (Lighthouse International, NY). Per study design, the following endpoints were prospectively defined to indicate study success, and were evaluated using the three-month results:

Major safety endpoints and target values

•BSCVA (1): less than 5.0% of subjects lose more than two lines of BSCVA at the time point of stability

•BSCVA (2): less than 1.0% of subjects have BSCVA worse than 20/40 at the time point of stability

•induced astigmatism: for spherical treatments, induced manifest refractive astigmatism of more than 2.0 D to occur in less than 5% of subjects

Effectiveness endpoints and target values

•UCVA: UCVA of 20/40 or better to be achieved in at least 85% of eyes at the time point of stability

•refractive predictability: at least 75% of eyes to achieve MRSE of ± 1.00 D, and at least 50% of eyes to achieve MRSE of ± 0.50 D, at the time point of stability

•astigmatic corrections: the mean ratio of surgically-induced refractive change to intended refractive change (SIRC/IRC) falls within the range of 0.85-1.15, with an SD of not more than 0.30 D.

Results

Cohort description and accountability

The report cohort consists of the three-month results of all patients enrolled at the start of the study in February 2001 through September 15th, 2001. During that interval, 815 eyes of 418 patients were enrolled.

The male-to-female eye enrollment ratio was 422 (51.8%) to 393 (48.2%); the mean age 37.9 ± 9.7 years. Caucasians accounted for 758/815 (93.0%) of enrolled eyes; there were 12 (1.5%) black, 12 (1.5%) Asian, 20 (2.5%) Hispanic, and 1.5% classified as ‘other’ eyes. Approximately two-thirds (554/815, 67.9%) of eyes had a history of soft, gas permeable, or PMMA contact lens use.

Data analysis was performed using data reported through March 1st, 2002. As of that date, and excluding eyes that had been discontinued from the study, all eyes had had enough time elapse to be reportable at three months and be included in this report. Seven eyes were discontinued from the study, leaving 808 eyes eligible for the three-month examination. Of these, 751 were reported, making a reporting accountability rate of 751/808 (93%). Spherical treatments account for 241/751 (32.1%) and spherocylinder treatments for 510/751 (67.9%) of the reported eyes.

Preoperative refractive distribution

The preoperative refractive distribution for the 751 reported eyes extends up to 11.99 D myopia and 6 D astigmatism (Table 3). Most eyes (622/751, 82.8%) have less than 7 D spherical error; 748/751 (99.6%) have a cylinder of 4 D or less.

Uncorrected visual acuity

UCVA results are reported for eyes targeted for distance vision. Twenty-four of 751 (3.2%) of the eyes seen at three months had been targeted for monovision (spheroequivalent of less than -0.50 D), leaving 727/751 (96.8%) for this analysis.

Overall, the mean visual acuity was 20/17.4 (SD, 20/27.0 or 1.35 lines), with 431/727 (59.3%) achieving a UCVA of 20/16 or better. The 20/16 rate was better in sphere corrections (166/231, 71.9%) than in spherocylinder corrections (265/496, 53.4%, p < 0.001 using chi-square analysis). Rates for 20/20 were 627/727 (86.2%) for all eyes, and again better in spheres (219/231, 94.8%) than in spherocylinders (408/496, 82.3%, p < 0.001). Rates for all eyes, spheres and spherocylinders, were

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Table 3. Preoperative refractive distribution at the spectacle plane (14 mm) for sphere and cylinder components of the refraction

Table 4. Breakdown of UCVA results for all eyes, spheres, and spherocylinders. The average outcome was better than 20/20 (20/17.4)

statistically equivalent at the 20/40 level, at better than 98%. Detailed results for distance UCVA are provided in Table 4.

Manifest refractive spheroequivalent

Manifest refractions were reported in 750/751 (99.9%) eyes seen at three months. Refractive results were calculated against the targeted outcomes, permitting inclusion of eyes targeted for residual myopia (monovision) in this report.

Results of the MRSE paralleled UCVA results. The overall mean MRSE was –0.14 D (SD, 0.39 D). For spheres, this value was –0.05 D (SD, 0.30 D), and for spherocylinders, –0.18 D (0.42 D). Outcomes for spheres were statistically better for both mean (p < 0.0001, Student’s t test) and variance (p < 0.0001, F test for variance).

The ± 0.50 D rate was 649/750 (86.5%) for all eyes. The rate for ± 1.00 D was 735/750 (98.0%), with only 11/750 (1.5%) eyes being undercorrected by 1.0 D or more, and 4/750 (0.5%) being overcorrected by more than 1.00 D. No eyes fell outside ± 2.00 D from target.

These results are detailed in Table 5 and graphed as attempted versus achieved in Figure 1.

Table 5. Detailed breakdown of MRSE outcomes at the three-month interval. Note that the mean outcome for spherocylinders was slightly more myopic than for spheres. Overall, 86.5% of eyes fell within ± 0.50 of the targeted amount

Fig. 1. Attempted versus achieved spheroequivalent. The parallel lines indicate the 1-D interval and the center line represents a linear regression of the data with the intercept forced to pass through the origin. The correlation (R²) is 0.96.

Best spectacle-corrected visual acuity

The average change in BSCVA was a gain in vision for all eyes (mean, 0.70 lines; SD, 0.87), spheres (mean, 0.80 lines; SD, 0.88), and spherocylinders (mean, 0.60 lines; SD, 0.86). The differences between the subgroups were not statistically significant. A gain of one or more lines of BSCVA was noted in 423/750 (56.4%) eyes,

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Fig. 2. Changes in BSCVA. A detailed breakdown of BSCVA changes at the three-month postoperative interval. Note that most eyes gained in BSCVA, and only 3/750 (0.4%) lost two or more lines (protocol target < 5.0%).

and one of two or more lines in 92/750 (12.3%) eyes. Interestingly, the BSCVA change did not correlate with the correction amount (R² = 0.0008, not significant).

A loss of two or more lines was noted in 3/750 (0.4%) eyes. One of these eyes had undergone correction for spherical myopia, the remaining two spherocylindrical corrections. No eye lost three or more lines of BSCVA, and no eye had a postoperative BSCVA worse than 20/40. One eye (a spherocylinder correction) had a BSCVA worse than 20/25.

BSCVA results are shown graphically in Figure 2.

Cylinder outcomes

Correction of astigmatism was attempted in all eyes with 0.50 D or more of preoperative refractive astigmatism. The mean preoperative cylinder amount was 0.73 D (SD, 0.75 D; range, 0-5.50 D). The improvement in astigmatism was statistically significant for mean (p < 0.001, Student’s t test) and variance (p < 0.001, F test for variance). The mean postoperative cylinder amount was 0.27 (SD, 0.35 D; range, 0-

2.50D). Cylinder outcomes showed a mean postoperative centroid4 of 0.03 D (SD,

0.31D).

Figure 3 depicts preand postoperative cylinder amounts using doubled-angle plots, and Figure 4 contains a scattergram of attempted versus achieved cylinder results.

Comparison to protocol targets

Target outcomes were defined to determine the success of this prospective study. The targets, with associated outcomes, are listed in Table 6. Each target was easily met in this series.

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It should be noted that additional targets exist in the protocol regarding stability and other measures that cannot be measured through analysis of outcomes at a single interval.

Discussion

The interim (three-month) outcomes presented in this report of 751 eyes undergoing LASIK for spherical and spherocylindrical myopia, operated on during an FDA IDE trial, easily meet the protocol targets for safety and effectiveness (Table 6).

Since the study protocol follows the published FDA guidance for the evaluation of excimer lasers, this report suggests that the clinical results will meet FDA requirements for the pre-market approval application of the WaveLight Allegretto Excimer Laser System. However, some protocol targets, such as refractive stability, could not be evaluated in this report since they depend on multiple observations. Final assessment cannot be made until the study is complete.

This series is most remarkable for the excellent outcomes of UCVA, MRSE, and BSCVA. The protocol target for UCVA is for 50% of eyes to see 20/20 or better at the point of stability. The three-month results in this series show a 20/20 rate for all eyes of 86.2%. It was 94.8% in sphere and 82.3% in spherocylinders. The protocol does not include a target for 20/16. However, 59.3% of all eyes, 71.9% of spheres, and 53.4% of spherocylinders had a reported UCVA of 20/16 or better. This series exceeded the 20/20 UCVA target at the 20/16 level.

MRSE outcomes paralleled the UCVA results. The protocol target for ± 0.50 D is 50%. In this series, the ± 0.50 D rate was 86.5% for all eyes, 93.4% for spheres, and 83.3% for spherocylinders.

In this series, an improvement in BSCVA of 0.7 (SD, 0.87) lines was seen for the overall group. A gain of one or more lines of BSCVA was experienced in 423/750 (56.4%) eyes. Previous authors have noted the expected improvement in BSCVA on correction of myopia, due to the removal of spectacle-induced image minification.8,9 The degree of expected improvement varies with refraction, spectacle characteristics, and vertex distance. In this series, a change in BSCVA did not correlate

Table 6. Outcomes compared with stated targets. All targets were easily met

* For eyes targeted for distance vision.

# For eyes undergoing correction of spherical myopia.

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Table 7b. Comparison of the outcome of this series (first listing) to other lasers in the similar FDA studies described in Table 7a. Items underlined in bold differ significantly from the WaveLight Allegretto results, using a chi-square test

Items underlined in bold differ significantly from the WaveLight Allegretto results, using a chisquare test

1.Range indicates range reported, and may not reflect FDA approval range.

2.For eyes targeted for distance correction

3.NR = Not reported

4.Study sponsor CRS Clinical Research, Scottsdale, AZ

5.p < 0.001

6.p < 0.01

with treatment amount, so the mechanism for the improvement seen in this series may relate to other factors.

The results for spheres were significantly better than for spherocylinders for UCVA and MRSE. The results were statistically equivalent for BSCVA changes. The mean spheroequivalent for spheres was closer to plano than that for spherocylinders, which suggests that the better UCVA outcomes for spheres were in part due to the better nomogram accuracy in this group. However, the refractive scatter (MRSE variance) of spherocylinders was significantly greater for spherocylinders than for spheres, so the mean outcome cannot completely explain the differences. Some other factors besides the mean outcome appear to reduce the

140 G.M. Kezirian and K.G. Stonecipher

refractive predictability in spherocylinders. That the BSCVA results were statistically equivalent in both groups suggests that the difference is limited to effectiveness (predictability) and does not threaten safety (loss of vision).

Table 7 provides a comparison of the three-month results in this series with those of four other lasers for myopic spherical and spherocylindrical LASIK corrections in similar treatment ranges. Comparisons are provided for the outcome targets UCVA 20/20, MRSE ± 0.50 D, and BSCVA loss of two or more lines. The results for the other excimer laser were from comparable FDA studies, published by the FDA as part of the regulatory approval process in a document known as the ‘Summary of Safety and Effectiveness’ for each laser. These documents are provided over the Internet; links are provided for each laser in Table 7a.

Table 7a compares the series characteristics with each of the comparison lasers. All series were performed for spherical and spherocylindrical myopia using LASIK. Ranges were comparable to the present study, with slight differences at the higher ranges of treatment. However, in all the series reported, the present study included, eyes in the higher ranges were represented in smaller proportions compared to the overall group, thus minimizing the importance of these differences. Two lasers (LadarVision and Technolas 217A) were flying spot lasers similar to the WaveLight Allegretto, while the Nidek EC 5000 uses a scanning slit, and the Visx Star S2 is a broad-beam laser. The results used in Table 7 were from the time point of stability, as defined in the Summaries of Safety and Effectiveness. For the flying spot lasers, this was the three-month examination. For the Nidek and Visx lasers, the six-month examination was used.

Table 7b compares the results of each laser for the three endpoints of UCVA, MRSE, and BSCVA. The results for the effectiveness targets of UCVA and MRSE in this series were significantly better than for the LadarVision laser, Nidek EC5000, and Visx Star S2 in all subgroups (all eyes, spheres, and spherocylinders). The results for MRSE in this series were significantly better than with the Technolas 217A for all eyes and spheres, but not for the spherocylinder subgroup. The results for UCVA in this series were significantly better than with the Technolas 217A for spheres, but not for all eyes taken together, or for the spherocylinder subgroup. In no category was the WaveLight Allegretto significantly worse than any of the other lasers.

In summary, the three-month interim results presented in this prospective formal trial exceed published FDA targets and compare favorably with earlier series using other lasers. The results for other protocol targets, subjective patient questionnaires, and stability analysis await further follow-up.

References

1.Pallikaris IG, Siganos DS: Excimer laser in situ keratomileusis and photorefractive keratectomy for correction of high myopia. J Refract Corneal Surg 10(5):498-510, 1994

2.US Department of Health and Human Services, Food and Drug Administration, Center for Devices and Radiological Health: Checklist of Information Usually Submitted in an Investigational Device Exemptions (IDE) Application for Refractive Surgery Lasers. October 10th, 1996

3.Pallikaris IG, Siganos DS: Laser in situ keratomileusis to treat myopia: early experience. J Cataract Refract Surg 23:39-49, 1997

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4.Holladay JT, Moran JR, Kezirian GM: Analysis of aggregate surgically induced refractive change, prediction error, and intraocular astigmatism. J Cataract Refract Surg. 27(1):61-79, 2001

5.Waring GO III, Carr JD, Stulting RD et al: Prospective randomized comparison of simultaneous and sequential bilateral LASIK for the correction of myopia. Ophthalmology 106:732738, 1999

6.Holladay JT: Proper method of calculating visual acuity measurements. J Refract Surg 13:388– 392, 1997

7.Holladay JT, Cravy TV, Koch DD: Calculating the surgically induced refractive changes following ocular surgery. J Cataract Refract Surg 18:429-443, 1992

8.Maldonado-Bas A, Onnis R: Results of laser in situ keratomileusis in different degrees of myopia. Ophthalmology. 105(4):606-611, 1998

9.Kawesch GM, Kezirian GM: Laser in situ keratomileusis for high myopia with the VISX star laser. Ophthalmology 107(4):653-661, 2000