Dr. L. Jay Katz: I'm Jay Katz. I'm from the Glaucoma Department at Wills Eye in Philadelphia. And we're going to talk about the SLT/MED trial, which was an initial treatment study that was done and we've published on

But, before we get to that, I thought we'd go through a little bit of the evolution of understanding laser trabeculoplasty in terms of where we are today, how it works, because over the past 30 years of having laser trabeculoplasty, we've still been learning on how it actually lowers eye pressure

It's fascinating. All the kind of interesting things that are fitting together, multiple things that probably work together in lowering eye pressure after laser trabeculoplasty are being more and more clearly identified

And then there's an evolution of how we've used laser trabeculoplasty in our clinical practice that I thought I'd go through

And then we talk about laser trabeculoplasty as an initial option for treatment in open-angle glaucoma. And I think there is a role for it. And we'll talk about that towards the latter part of the discussion

Whoops. So, just as disclosure, I have worked with Lumenis as a speaker and also received research funding. And they are the makers of the SLT

I'm not political. And I know that everybody's a little bit abashed by the recent election and whether your Democratic or Republican. But, I put this up here because, to me, George W. was a fun guy. And he would make up words sometimes

And one of the things that he made up when he was asked about how he felt the press was dealing with him, he said the press misunderestimated him. And that's a made-up word

But, it's a good one. I like it because it has two different meanings. And they both apply I think to how we have approached laser trabeculoplasty

We've misunderstood its role. And because of that, we have underestimated its value

So, I say that because, traditionally, all of you--I'm willing to venture a guess--the way you were trained to do laser trabeculoplasty is when you've failed medication, correct

So, if I told you that you had somebody on multiple drug therapy, except a prostaglandin, and you added prostaglandin after you're on three other meds, would it work well

And the answer is no. It doesn't work as well as if you did it first as monotherapy. And that's exactly the theme of laser trabeculoplasty, that it works much better when it stands alone, not when you've added it in a situation where somebody is doing very poorly, they're failing medical therapy, and you throw that into the mix

I've even heard people say that laser trabeculoplasty was a sham procedure because it didn't seem to work in anybody

Well, that's probably a guy who has a tertiary practice, referral practice with people who are doing poorly with glaucoma. They try it as a last gasp. And again, no surprise, it's not going to work in that setting particularly well

So, here is the traditional treatment paradigm that has been in effect for many years, medicine, medicine, medicine, medicine, laser, surgery

And the question is, "Should we be doing it that way in each and every patient?" And the answer is we should consider alternatives to that stepping paradigm, at least in some of the patients

All of you are aware that, years ago, Jim Wise from Oklahoma was the first guy really to show how we could lower intraocular pressure effectively and long term by doing argon laser trabeculoplasty

And his settings back 30 years ago are essentially the same settings that are used for argon laser even until this day

But, we've noticed also in subsequent studies in Boston and Philadelphia by George Spaeth, my partner and mentor, that there's an attrition over time

If there's failure in the first year, certainly doesn't seem to work well maybe in 20 percent in their populations, and then there's an attrition rate of 10 percent per year with loss of efficacy

And we know that, in some people, there may be a transient benefit with laser trabeculoplasty. And these are, again, in patients that often are on treatment already with medical therapy

And over the years, we've known that there are limitations with argon laser trabeculoplasty. It's going to have a modest effect, like we've talked about. If you're already on multiple drug therapy, you're going to lose effect over time

And because an argon laser is thermal, you're actually damaging the outflow drainage system of the eye with the argon laser. That's not the site where you're improving outflow where you burn with an argon laser. It's the tissue adjacent to it that we think is helped by the argon laser

So, if you keep using an argon laser repeatedly, let's say you get an effect the first time. And two years later, the pressure goes up. And you decide to do another round of treatment

Well, what we found out clinically is that, what will happen is that you'll get a paradoxical elevation of pressure that's sustained. And that's actually how you create an animal primate model of open-angle glaucoma

You just keep using the argon laser repeatedly. And you get a sustained elevation of pressure in primates. And then you can test drugs, for example, or surgery and see how it works in an animal model

There's the--I'm sure you've seen these pictures of an argon laser burn of the trabecular meshwork. This is scanning EM. You see that crater thermal melting

And this is obviously not going to be the area that you get the benefit. You can imagine if--with all that thermal destruction in the cadaver eye, in an actual in vivo situation, you're going to get a lot of scarring in that area, which is what happens. And that area's going to be very limited in outflow

Sometimes, people have even identified membranes in response to an argon laser that'll actually cover the trabecular meshwork. So, again, if you have a membrane forming there, it's going to be difficult for the aqueous to get through that

And it's interesting. In the infancy of argon laser trabeculoplasty, it was noted that, if you had pigment in the angle, you had a better chance of a response with pressure reduction than if you didn't have pigment

So, Mark Latina is right here, who's the father of SLT. Mark was a clever guy. He worked in Boston with some people who were doing selective photothermolysis for dermatology. He said, "This is exactly what we should be applying in glaucoma

"We should get a laser wavelength that's very, very, very specific for the pigmented tissue. So, can we target that and not damage the adjacent tissue? That would be ideal.

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So, that's what is his mission. And he was successful. He looked at different wavelengths. And he found that the wavelength for the SLT, frequency-doubled Neodymium Yag laser, that wavelength was exquisitely sensitively absorbed by melanin

So, you had most of the thermal effect limited just to the pigmented tissue, the pigmented cells in vitro. And he was going to apply that clinically. And that's led to the birth of SLT, so again, pigmented cells affected, nonpigmented cells not touched

And that's what he showed in vivo, in culture. So, the red cells here all labeled in red are dying or dead. That was irradiated with an argon laser. And then on the other side, with an SLT irradiation, he only had limited death or destruction of cells that carried melanin

The adjacent tissue, which is in green, seemed to do just fine in vitro

Kramer, Noecker took some cadaver eyes and also went ahead and showed what the typical argon laser burn would be and compared it with SLT

And the same thing, now in a cadaver eye preparation, there's a thermal burn with argon. And there's the relatively intact SLT irradiated tissue

Well, that's--we talked about in vitro. We talked about a cadaver prep. What about in vivo live? Well, in animals, it's not quite humans. So, we actually undertook a study, Dr. Alvarado in San Francisco and then our institute at Wills, we did a study in vivo

And how did we do that, you know, and get tissue, obviously? You're looking at it here. These are patients that didn't have glaucoma. They had a choroidal melanoma. And they were cared for by our oncology group, Carol and Jerry Shields, who are the directors

And these patients were kind enough to allow us to do heavy SLT irradiation over 180 degrees, and the other side was left as a control

Dr. Alvarado then got the anterior segment sections when these patients were nucleated for their melanoma

So, we sent these off. And we didn't tell them which side had SLT and which side was the control. He did not know

So, here, you could see the control side that you have pigmented cells there labeled with the arrows. So, you see these nice pigmented cells in vivo, live tissue now sectioned

And there on the other side is SLT-treated area. And there's a paucity of pigmented cells. So, this confirmed the whole hypothesis that you could actually blast away with an SLT, preserve tissue, but really target only the pigmented cells, and they disappear. They are the ones that have been destroyed

And that's going to be the critical pivotal initial step in a cascade of events that leads to lower pressure

Here again is a scanning EM, the control side. You can see the trabecular beams. And this is a scanning EM of tissue from a human, like we said. And there on the other side, you see the beams are pretty much intact as well. There's a little bit more cellularity or inflammatory cells in the region

Now, how does laser trabeculoplasty work? Well, nobody knows for sure. And here are several of the theories. And they may all be correct

The first one was really--started back when Jim Wise did lasers, is that, by creating a contraction burn with an argon, you're stretching the adjacent trabecular beams and opening up flow, a purely mechanistic, you know, structural change that improves outflow, kind of like maybe a pilocarpine effect, if you will, you know, stretching things there

Well, then there are also these theories about endothelial cell replication. Just like in the cornea, our endothelial cells in the cornea don't normally replicate. That's why we get, you know, aphakic, pseudophakic bullous keratopathy, or Fuch's corneal dystrophy with edema is that you lose a critical number of endothelial cells, you get a swollen cornea

Well, in the meshwork, it seems that you need a critical number of endothelial cells as well. And you lose these cells with time, aging. But, you may accelerate it in a glaucoma situation

So, if you can get a repopulation with endothelial cells in the meshwork, that may lower pressure. So, that's another theory

And then finally, there are various biochemicals that improve outflow. And if you can upregulate them, then you get--again, get a drop in intraocular pressure, all of which is by improving trabecular outflow

And there have been clinical trials showing that, yes, the way lasers work is improving trabecular outflow

So, here's the mechanistic model of the stretching, the first theory

Here's an animal model showing that you can induce endothelial cell replication by using an argon laser that was done in Oregon with Van Buskirk's group

And here, again, is all the theories about, you know, trying to improve flow to get into Schlemm's canal

Now, when you think about this, what's the problem with open-angle glaucoma? The problem is that there's a higher resistance than you would like in the trabecular meshwork and the juxtacanalicular tissue before you get to Schlemm's canal. That's the problem. That's the pathology

Now, laser seems to be directed at improving that problem. So, in a sense, it's trying to reestablish the physiological outflow pathway by whatever mechanism, whether it's stretching, whether it's cellular, or whether it's biochemical

And people have shown that there is an alteration in the various glycoproteins and the meshwork in response to laser

People talked about upregulating cytokines in response to laser that seemed to really improve outflow

And so, this is a nice little model here from George Alvarado, again, from San Francisco, who's done a lot of great work

He's a glaucoma clinician. But, he's also a bench scientist and done great work in understanding laser trabeculoplasty and, again, showing all the different kind of theories kind of bunched together here making sense as a cascade of events

He's shown very clearly that, in response to laser trabeculoplasty, SLT in particular, that you get monocytes and macrophages that are recruited to the trabecular meshwork that orchestrate a series of events, he thinks, that lead to an improvement in outflow

So, there's a release of cytokines. There's the recruitment of these macrophage to the trabecular meshwork and subsequently have a better outflow

He's done some neat studies, where, you know, he takes tissue that was irradiated with SLT and takes the fluid out of the in vitro culture and throws them into the culture with Schlemm cell endothelium

And they separate nicely. So, the adhesions separate

He does the same thing with Xalatan, same thing. They separate

He uses timolol, brimonidine. They don't separate

So, he actually theorizes that the pathway by which SLT works is by improving outflow through the trabecular meshwork, which we know prostaglandins do as well as uveoscleral outflow. They do--it does both

All right. So, you're all familiar, I think, with these settings. Only things that you can do with the SLT in terms of adjusting is power and the number of applications. Those are the only variables. It can't change the spot size

So, what we do is change this and this depending on the clinical situation

Now, I wrote over here zero point millijoules is kind of the starting energy. And I confess I don't do that anymore

A lot of people have gone up. Some people like me have gone down. And I mentioned George Alvarado and others, another group from--actually from Asia recently, reported the same thing

We've gone way down on the power and increased the number of shots

I do 100 shots at low energy, 0.3 to 0.4. Other people go higher

George Alvarado, I think his latest treatment paradigm is 0.3, 0.4, 200 shots, and seem to get good response and a lower chance of a pressure spike, which is the one major concern with laser trabeculoplasty

If you have a lot of concern about a pressure spike, go down on the shots. Treat 180 degrees, for example, fewer number of shots

And who should you worry about? You should worry about people that are heavily pigmented, pigmentary glaucoma, pseudoexfoliation. You should also worry about somebody who's on multiple drug therapy with a really bad nerve, bad visual field. I would be careful. You don't want to really risk a major pressure spike

And by less energy and fewer shots, it's safer. You can always go back and do more later

Well, how does laser trabeculoplasty compare when you're looking at SLT and ALT

So, this is one of the first studies by Karim Damji in Canada. There's no difference in efficacy. It seems to work just as well, not any better, not any worse, compared to ALT the first time around

That's what Karim has shown in this initial study. And even followed for years out, that seems to hold true

This is an interesting study done by the Duke group. So, this is Duke University. And they published this in the Journal of Glaucoma, great journal

This is retrospective. This is their initial experience with SLT

So, what I want to point out--so, they have almost 100 patients. And they called failure a drop of less than three millimeters or didn't achieve 20 percent reduction

And at 14 and a half months, that failure rate with those modest goals was right around 90 percent

Say, "Wow. That's really horrible." And I agree. It is horrible

But, look at their study population. Two-thirds were on two or more meds. They're already like--these people are on their--they're hurting

The pre-op pressure was 17.6. When you have pressure that low to start with, you're not going to get much of a drop with anything medical or laser

And then one-third had less than 35 spots. I mean, nobody recommends that as a routine treatment. I can't imagine everybody had pigmentary glaucoma. They didn't

So, I think that they were doomed to fail because of those kind of reasons

In fact, the Duke group right now is very emphatically in favor of SLT

So, despite these dismal results, these dismal results were because this was a horrible population that was doomed to do poorly for those reasons

Interesting, this is an old paper I pulled up from University of Florida. They were looking at adding a third or fourth glaucoma medication

What is the chance of them achieving a 20 percent pressure reduction sustained for up to a year? Well, less than 25 percent

I mean, so, laser's the same way. I mean, if you're on multiple-drug therapy, you're not going to get that much of a response. You have to be really realistic about that

This is a group from USC, Brian Francis. They were--they thought of using laser in a different way. They said, "Here are some patients. We're not sure about their compliance. They're not particularly happy because of side effects. Let's see if we can substitute laser for medication.

So, about 80 percent of the time, they're able to do SLT and stop two or more meds, two or more meds

Again, this is a population where they're worried about compliance. They're having side effects. So, they're probably not complying. This is a great substitute therapy

Like I said, there was very little to support the use of repeat ALT. But, repeat SLT is very intriguing. And that's still controversial to some extent if you talk to various people. But, I think this makes theoretical sense

And there's preliminary information that, again, there might be a role for repeat SLT because it doesn't cause any thermal injury to the tissue

This is the first published paper from the Yale group showing that they could get a successful drop with repeat SLT, meaning at least a 20 percent reduction in patients, many of them on medication. And about 43 percent had a reasonable drop in their pressure with a repeat SLT application

There's a collaborative retrospective look at repeat SLT with these five institutions. And again, we're able to show that, yes, if you looked at the group that seemed to have a response the first time and you did it again, well, you know, you could get a successful outcome, I mean, depending on which criteria you use

So, I think that you can get a drop in pressure with repeat SLT. It does happen. And we do it in the right circumstances today

All right. Well, that's kind of a long preamble to get to talking about primary therapy with SLT. So, when would you think about using that and why would you

Well, there are the big four reasons. You want to look--if you're comparing something like SLT with medication, you want to look at efficacy. How does it compare in terms of lowering pressure

What about compliance? That's a huge problem for us in glaucoma with medical therapy

Safety, what are the side effect profile

And then finally, cost, nowadays, everything is going to be looked at with a very critical eye in terms of cost effectiveness

All right. Well, let's look at efficacy. Let's go back historically just a moment to the glaucoma laser trial. This is an any-eye sponsored study that compared argon laser trabeculoplasty against timolol. That was the dominant drug first line back then. This is a 1980s trial

And look at what they showed. By very strict criteria, by very strict criteria, laser was able to control almost half the eyes at two years and dropped off with attrition to 20 percent at seven years, so one out of five laser alone

You say, "Well, that's okay.

Well, look at medication, timolol, our best drug at the time, 30 percent controlled at two years with timolol alone. And that dropped down to 15 percent at seven years

Now, this had--this study was criticized for a lot of reasons, one of which was the crossover effect, meaning these patients with newly diagnosed open-angle glaucoma that were randomized to get ALT in one eye and timolol in the other eye--that was the study design--we know that there's a crossover effect with timolol. So, timolol in one eye lowers pressure in the other eye

But, what we didn't realize back then is that, actually, there is a crossover effect with laser trabeculoplasty as well. That's been shown

If you laser one eye, you actually can get a drop in the other eye, a little bit

And at first, we didn't think it was real. But, I'm convinced that's real now

Now, here we come up to modern day trials. So, there are a flurry of studies, not ALT, but SLT now, looking at it as primary therapy

And there's a study from the U.K. by Dr. Nagar, Dr. Hutnick in Canada. And then recently, here in the United States, we've done the SLT/MED trial

And all of these kind of share the same basic thought, that you lower pressure about the same as prostaglandins at roughly one year, so about anywhere from a 25, 30 percent drop in intraocular pressure

Now, in the U.K. study, they actually did a randomization between 90 degrees, 180, and 360 as the initial treatment. And a fourth arm, they received Xalatan or latanoprost

And what you see, there's kind of a dose-response curve with that--the 360 being the most effective treatment with SLT. And that seemed to be equivalent to latanoprost and success in lowering intraocular pressure

The SLT/MED trial that was undertaken here in the U.S. and Canada involved doing 360-degree SLT as the initial therapy, and the group randomized for laser in both eyes, so both eyes

Or, if they were randomized to medication, they would get medication for both eyes

And if you failed the SLT, you got another round of SLT before you went to medication

And medication, we kept medication as long as we could before we had to go to SLT. So, we kept switching and adding meds

And the way we had a target pressure in mind here, we borrowed a formula from the Collaborative Initial Glaucoma Treatment study, which was an NEI-funded study comparing trabeculectomy versus medication as the initial therapy

And they--that formula depended on what was the starting pressure and how bad was the visual field? And that would spit out a number. And that number could be different in the same patient for the two eyes depending on that formula. So, that's what we had to get to in this study

And here are the simplified results. The starting pressures were relatively the same, right, around 24, 25. And the pressure drops, again, were statistically similar

So, what was not similar, though, is that, in the SLT arm, they were stepped to a second round of SLT only 11 percent of the time, whereas, in the medication arm, a quarter of the patients or more were stepped to two additional medication

So, the efficacy, everything to date, at least going out to the year shows that efficacy seems to be the same as our best drug class prostaglandin

Well, what about safety issues? Well, safety, as I mentioned before, I think you're worried about a pressure spike. There are more rare things that could happen, like persistent inflammation, a transient shift in refraction. I mean, there are some unusual things that you might see

But, by and large, we're really worried about pressure spikes. And if you use relatively low power, fewer shots, and you use alpha agonists in the perilaser period, you're less likely to get a pressure spike

And as I mentioned, if you have an angle that looks like that, heavily pigmented, be very careful. Turn the energy way down. And you may want to trade 180 degrees or even less as a test run in those patients because, in this series collected in Canada, they had four patients that had sustained major pressure elevations

I mean, these are patients that go to 50. And you have to go to the operating room emergently

And I've had one case like that myself where that happened. And she had to have an emergent trabeculectomy, back when we didn't really realize the inherent danger with SLT

It's just absorbed so well by the pigment, you have to be careful

Well, what about side effects with medication? You all are familiar with that

We have issues of just cosmesis, hyperemia. And not to belittle it, some people just--you know, they're in sales. And their eyes are red. And people are saying, "You're drinking or smoking, and what's wrong, not sleeping?" People just don't want to be out there with really beet-red eyes

There are also ocular situations where you have blurred vision, discomfort, lid erythema, blepharitis. So, we're all familiar with that with the various potential offenders

And then finally, especially with beta blockers and certainly with oral carbonic anhydrase inhibitors, you have some serious issues with systemic toxicity

You know, people have died from using glaucoma medication. It's a fact

Fortunately, it's rare. And if you're careful, you can keep that to a bare minimum. But, that's always an ever-present danger with using topical medication and oral medication for glaucoma

Well, what about adherence and compliance? And I won't belabor this too much with medication. There's a wealth of information about noncompliance, nonadherence with glaucoma medication

There's an old study from the '80s by Dr. Michael Cass in St. Louis at Barnes, Washington U

And what he did was he gave bottles that had little electronic chips inside that could monitor when the patients were using the medications at home. But, he didn't tell them that they--he'd put that monitor in there

And when they came back, he said, "Well, are you taking your medication?" And then he would look at the monitor and see if they really were

And it turned out patients way overstate how compliant they are

And number two, he polled the doctors and asked them, "Do you think this patient's compliant, or is this patient compliant?" before they knew the results. And as doctors, we're very, very poor in predicting who's going to be compliant

So, we don't know who's really going to use it and who's not

Now, people say, "Well, what if the drugs were free? That would certainly help a lot.

Well, it may. I think it would help if everything was free. But, even if you're--if it's free, about half the patients in one study--they were given free medication, didn't cost them a dime, and about half these patients, they used the medication, which was once a day only, so it's an easy treatment, with Travatan, they used it less than 75 percent of the time

So, we know that there's a huge issue. And our best estimate in the real world is that somewhere between 50 to 75 percent of our patients are reasonably compliant. Nobody knows the exact number

Laser trabeculoplasty is obvious. It's 100 percent compliance. You've done the treatment

Finally, cost, there've been a number of different models that have tried to figure out comparative costs, looking at medication, looking at laser trabeculoplasty, Canada, United States--I was involved with that one--and here's from Australia

And all three of those--and these are from a few years ago --said, "Yes, laser seems to be a more cost-effective strategy in treating glaucoma than starting with medication.

Well, this is actually even more recent from the Archives this year, where two different studies have tried to look at comparative costs between SLT and even generic latanoprost, the cheapest prostaglandin out there

And even here and after a certain period of time, assuming --making certain assumptions on success rates as monotherapy, even here in these modeling analyses, it seems that, again, SLT seems to be a reasonable choice if you're worried about cost of treatment

So, if I can summarize for you, I think that what you should remember--and you probably already know--is that the pressure reduction, whether it's adjunctive or as primary, seems to be just as good as maybe our best drug class out there, meaning prostaglandins or beta blockers

Admittedly, laser trabeculoplasty does have a waning effect over time. There's some encouraging information about SLT in particular being repeatable

But, you know, in glaucoma, we're always delaying things. There's always a delaying tactic. That's what we do in glaucoma

With regard to safety, compliance, and cost, I happen to think that that--when we're on those particular issues, really falls in favor of laser trabeculoplasty

And therefore, is it reasonable to change your treatment paradigm to use laser earlier and maybe even as initial monotherapy? My conclusion is, yes, that you should at least offer that

Now, in my practice, I can tell you that the majority of patients prefer medication first. And it's complex as to why there are many reasons. But, I think that number's gone up, where they would prefer monotherapy with SLT first. And I think that's going to change in the future

I think more and more patients as they become more educated about it and as you become educated and aware of a lot of issues that we've talked about may feel more comfortable offering that as a first-line treatment option and, even if it's not a first-line treatment option, maybe doing it earlier than we traditionally have done it in the past