Preservative-free glaucoma drops with Gavin Docherty, ep 41

Preservative free glaucoma drops with Gavin Docherty, ep 41

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[00:00:00] Introduction to Talking About Glaucoma

Robert: You're listening to talking about glaucoma. Bringing the latest advances in glaucoma eye care providers and patients since 2009. Visit TalkingAboutGlaucoma.com for more details about each episode. I'm Rob Schertzer, a Vancouver based glaucoma specialist and educator, and we are. Talking about glaucoma. 

[00:00:23] Welcoming Dr. Gavin Docherty

Robert: Gavin Docherty. Welcome to the show. 

Gavin: Thank you very much for having me, Rob. Appreciate the invitation.

Robert: It's great to have you here. We've been trying to do this for quite a while. I know you're incredibly busy with managing a massive, uh, catchment area in the BC interior.

Gavin: Yeah, well, we were just discussing how you used to manage all of the province. So, um, thanks for acknowledging that. Um,

Robert: I'm glad that's passed on to you young ones now.

[00:00:56] The Growing Problem of Glaucoma

Gavin: yeah, well, I think, you know, all the studies just show [00:01:00] glaucoma is a, a growing problem. And despite having more surgeons than say 10 or 20 years ago, I think we still need more to adequately address the problem. 

[00:01:09] Preservatives in Glaucoma Medications

Gavin: So it's, you know, Nice to be here and talk about preservatives and preservative free therapy for glaucoma, because I think that's an important part of it.

 Initially we felt preservatives were required for drop efficacy and absorption. So it's actually put in specifically into the drops to try to improve drop effectiveness. You know, drug delivery on initially. I think it was required by FDA. You probably know better than myself.

But when I was reading up on this, I was required by FDA to have the preserved as one to ensure it was safe and wouldn't get causing infection.

Robert: Absolutely.

Gavin: As part of, uh, being able to manufacture and provide this in a safe way. And then number two, it was thought that it was required or necessary for drug efficacy.

And I think there's lots of studies now that show it's not [00:02:00] required to have preservers and drops for drug efficacy. And there are ways to deliver it preservative free that, um, help prevent infection. So we address that FDA concern and that still allow, um, Drug delivery in a way that's going to help us treat glaucoma and in a way that will reduce disruption of the tear film and other side effects from drops like hyperemia, for example.

 As you said, we now have more options for preservative free, uh, but I think a lot of us aren't really aware of why we should use preservative free. 

[00:02:35] Studies on Preservative-Free Therapy

Gavin: Um, so I have, I can talk about some of the different studies if you want, but basically there are studies now that show that you can change to a preservative free in class molecule, so like for prostaglandin is the one that has the most research for this, and you can achieve similar pressure control, but you get improved compliance, and mostly I think because there's reduced side effects such as Burning, irritation, [00:03:00] and redness, which results in improved patient satisfaction and more likely to take the drop.

So I think it was, uh, Dr. Cindy Hutnick. I heard this first from him, he says, we take a asymptomatic patient, tell them they have a disease, and then make them symptomatic with our treatments, which is the big question. problem for early glaucoma.

Robert: Right. Especially, especially when it's a disease where patients have, like you said, they're asymptomatic. Uh, they don't know why they should be on medications. And that, if we're creating a new problem for them, why would they be compliant? Absolutely.

Gavin: So trying to get patient buy in, it doesn't help if we have drops that make their eyes red and uncomfortable. And Preserve Free isn't perfect, but at least it's a step in the right direction to try and address that concern. And we've been trying this for a long time to try and improve our drug delivery with, you know, gentler preservatives, such as like, you know, Polyquad for Travitan and [00:04:00] Travitantimolol for a while was marketed as one that was gentler on the ocular surface.

And then if we look at Bermonidine, uh, if we have Bermonidine with Purite versus Bermondi with Purite. BAK, there's some studies that suggest there's actually reduced incidence of allergy or allergic conjunctivitis with the purite. So it does seem like the type of preservative, if it is present, does make a difference.

And unfortunately, it seems like benzoylchlorine chloride or BAK, the most common one seems to be the most problematic, yet it's the most prevalent in our drugs.

Robert: So yeah, you might as well quote some of the studies that you had in mind. I've heard you talks at several different, uh, conferences about free medications. So I know you're, you're well armed with the studies.

Gavin: Yeah,

Robert: fire away.

Gavin: it's a topic that I've found really interesting, um, not only in our clinics and efficacy, but also I think it helps us. Maybe have another [00:05:00] approach to understanding the pathophysiology of glaucoma. 

[00:05:03] Impact of Preservatives on Eye Health

Gavin: So just for, uh, before we get into the studies that look at the specific classes, you know, why are the preservatives bad?

So if we look at what preservatives do to the ocular surface, you already mentioned they disrupt the tear film, they dablet damage epithelial cells, they damage goblet cells. There's some evidence that they may actually induce more rapid cataract formation in patients. That's actually in the Blue Mountain study, which is one we quote a lot for other, uh, glaucoma purposes.

and then they cause redness and irritation of the ocular surface. If you look even deeper, there are some studies that look at inflammation within the eyes on the trabecular meshwork, and some of these studies show that benzalkonium chloride, you know, one example of a preservative, um, actually enclauses inflammatory deposits within the trabecular meshwork, and that raised the implication that we might actually be damaging the outflow [00:06:00] system with our treatments.

Um, There's no solid evidence to say this is 100 percent a correct, you know, cause and effect, but, you know, I think as a glaucoma specialist, we all have seen these patients that have been on drops for years and stable, stable, and then they present one day, 10 or 20 years later, and their pressures are through the roof, and they're out of control, and then they need a filtering surgery, and their chondroctypas, you know, are gone.

in rough shape from years of treatment. Uh, and it might be that we are actually damaging the outflow system with preservatives. So it's a Band Aid solution that may actually lead to a greater problem down the road because we've damaged the eye's natural drainage system.

Robert: That's a great point.

Gavin: So the studies that we're looking at, um, the most common ones are, um, gonna look at side effects and adherence rates, and most common class [00:07:00] is prostaglandins. Uh, so there's numerous studies for this, but basically, um, the main one is with, uh, Couturat et al., and they look at the relative efficacy and safety of preservative free therapy.

latanoprost, um, for the treatment open angle glaucoma. And they basically showed that, uh, hyperemia is less, but the pressure reduction is very similar for preservative free versus, uh, preserved latanoprost. 

[00:07:32] Patient Compliance and Satisfaction

Gavin: So essentially you can make that in class switch, um, and have confidence that you're still going to be providing a good treatment effect, but hopefully reducing side effects for the patients and hopefully improving adherence rates.

Um, initially, when Preserve A Free came out, there was a lot of concern, mainly because of this thought that we talked about earlier. The initial thought you had that preservatives were required for the [00:08:00] drug to work led to a lot of resistance to accept preservative free as a, an alternative. So there was initially a lot of concern or hesitation to try these medications because if they don't have preservative, how will they penetrate the cornea?

How will they work? And that's because we, that's, we thought that was required. So a lot of these studies improve our confidence that we can use preservative free and still get good drug delivery.

Robert: Was, was the mandate for preservatives, was that FDA dictated? Not

Gavin: understanding is it was initially, um, just to provide like drug shelf life safety profile.

Robert: Right,

Gavin: And we have seen cases where I think it was just a year ago. 

[00:08:44] Challenges with Preservative-Free Options

Gavin: People got serious infections from eye drops and it turns out that was a preservative free drop in a not appropriate bottle. So it was in a The bottles for preservative free have to be specially formulated to prevent [00:09:00] bacteria from getting into them.

And, uh, unfortunately they didn't have that formulated bottle and the drops had bacteria and it led to serious consequences. So, uh, the FDA wasn't wrong that that's a safety concern.

Robert: And that was for an eye lubricant, right, not a glaucoma medication,

Gavin: Correct, not a glaucoma medication, but an eye lubricant, which, um,

Robert: which many of our glaucoma patients are on because their eyes are being messed up by all these glaucoma drops.

Gavin: Yes, exactly. No, I, we, I tell people to use preservative free all the time and then this happened and before the full story came out, I was greatly concerned that there might be a bigger issue, but it turns out it was just, uh, in the wrong delivery mechanism. Um, so if we're looking at, you know, tolerability metrics, uh, LME in 2018, looked at ocular symptoms, so hyperpnea, burning, [00:10:00] itching, discomfort, blurred vision.

Um, and again, as you, I mean, it's not surprising, um, but the studies basically show that patients have less ocular symptoms when they're on preservative free versus preserved eye drops. And I think that's the message on and on again. And even when you look at prostaglandin. Orbitopathy. So, uh, hyperemia and sunken eyes darkening around the eyes.

That seems to be less with preservative free as well. I haven't found a paper that explains that mechanism to me, but, um, there are studies that support that. Even the cosmetic side effects associated with, uh, prostaglandin seemed to be less.

Robert: Oh, that's interesting because I get my oculoplastics colleagues sending me patients to get prostaglandin analogs if they're coming in and their fat pads are starting to sink in.

Gavin: [00:11:00] Mm-Hmm.

Robert: So I wasn't aware of that association, but possible association with the preservative with that.

Gavin: Yeah. And the other thing is, uh, you know, even looking at different classes of prostaglandin, so. Uh, Bematoprost seems to be the worst offender for prostaglandin over top of these, so even switching them to, you know, latanoprost, or if we're in the States, travoprost, or um, tafuprost might be enough to reduce that.

So, the other, uh,

Robert: if the BAK has a similar effect at all to, Y dase, was, we used to mix that in with our lidocaine when we gave retrobulbar blocks allow it to penetrate through the soft tissue better.

Gavin: and that cause,

Robert: if the BAK is

down soft tissues.

Gavin: and allowing periorbital spread.

I haven't read that, but it makes sense in my [00:12:00] mind. I wouldn't be surprised if that might be a contributing factor. Uh, the other, uh, thing is, you know, preservatives, as we alluded to earlier, might be making the disease worse. So we talked about studies that looked at the trabecular mesh work and they're being Signs of inflammation in patients using preserves or animodels using preservative there was a study out of France and I can send you the link if you want to quote it, but this was a national database that looked at 1, 200 patients and they categorized them into three groups if they were preservative free on mixed preservative and preservative free medications or if they just had preservative medications

 Basically this study showed that the preservative free group had very low probability of requiring cataract or glaucoma surgery. And there was quite a jump to the mixed preservative group. And then the [00:13:00] highest group that required surgery was the preservative only group.

So there are studies that suggest that our preservatives are In fact, maybe increasing rates of glaucoma surgery and increasing rates of cataract surgery.

Robert: Interesting. Was that controlled for the length of time on the medications? Do you

Gavin: I'd have to double check the study. Um, these national database studies, I would suspect it was not controlled.

Robert: Just thinking if preservative free drops are newer and so patients on preservative free may They've been treated for a shorter period of time, but yeah, that would be really interesting to find out.

Gavin: I want to say it was Dr. Birt or Dr. Hutnick. I can clarify the reference again, but they also looked at BAK exposure and, uh, rates of surgical failure in trabeculectomy. And they found the more, BAK exposure prior to surgery, the not only the higher rates of failure, but the faster rates of failure.

And again, I'll, I'll send you the reference for that.

Robert: [00:14:00] that'd be great. Those are two people I would fully trust any work that they do.

Gavin: Yeah. Uh, sorry, Dr. Catherine Birt. That was her study. And that was in, um, the PESO study in Journal of Glaucoma 2013. Canadian reference. So that's good.

Robert: Woohoo.

Gavin: Exactly. Sometimes we do. Actually, we have a lot of good glaucoma researchers. Impressive, because I think it's harder to do research in Canada for various reasons.

But, um,

Robert: Yeah. So aside from the prostaglandin analogs we know of, uh, being available as preservative free, what are our other options? We have our drosolamide timolol,

Gavin: and we have, uh, dorazolamide, preservative free. And then we've got, um, latanoprost and bimatoprost, preservative free. So we don't have an alpha agonist, and we [00:15:00] don't have a single beta blocker. Although I will use Timoptic XE, which seems to be a little better tolerated, even with patients that have multiple.

drop or preservative sensitivities.

Robert: right?

Gavin: Uh,

Robert: to have preservative free Timolol that came in minims that it was not Merck produced. It was, I think, Chauvin from France, and that used to be imported into Canada. So it might still be available in other parts of the world.

Gavin: yeah. And I think, you know, they have Duokopt in, um, Europe, which is basically similar to, uh, timolol and dorazolamide, but it comes in a multi dose bottle, which that's one of the big complaints about preservative free in Canada is we all, they all come in single vials, which is a concern for. The environment and waste and for patients who are have, uh, you know, [00:16:00] rheumatoid arthritis or other issues with, you know, their hands and being able to instill drops themselves.

That sometimes is an issue for them.

Robert: You know, absolutely have a lot of patients like that.

Gavin: Yeah. And then, you know, that's just one barrier to preservative free, which, you know, uh, so environmental concern and the actual ability to apply the drops and then the cost. So preservative free, um, isn't generally covered by most plans or by MSP. So you have to apply for. Special authority and be able to demonstrate that they require these drops or had reactions to other drops.

Robert: For our listeners, MSP is our provincial Medicare system, which all patients are covered with

Gavin: Yeah, so a lot of our generics are covered. Um, so the patient gets them at reduced costs or doesn't have to pay for them depending on their coverage plan. So there are supposed to have basic medical service plan, which should cover them for basic things. And then [00:17:00] a lot of people will have secondary insurance, which enhances that coverage.

But for the glaucoma drops, the preservative free are often not covered. So that's a. A barrier to transitioning for some people.

Robert: for sure, actually come to think of it. We do have now Just came out this past year a preservative free multi dose But mataprost

Gavin: Yeah, so,

Robert: in terms of zymed.

Gavin: Zahmed, that one is, uh, definitely the multi dose bottle is an advantage, and I think a move in the right direction. Unfortunately, it is still a lot more expensive than the vertifree Litanoprost, I think, like, three more times the cost at this point.

Robert: Yeah, and even in our cost effective system here I'm finding A lot more complaints in the past year or so from patients of how expensive the drops have become. So,

Gavin: Well, I think in our, unfortunately, our current economy, uh, Canadians have been, hit hard and things are [00:18:00] tighter and you know the the drops for this asymptomatic disease are probably the first thing to be questioned

which it makes it hard as a glaucoma specialist because you you see people go blind from this and you don't want that for your patients but it gets frustrating trying to You know, with complaints about costs, because that's not technically our, I mean, it is a problem because our patients are not going to take the medications or don't want to take the medications, but technically, that's not a problem we created, or it's not something we have control over.

Robert: right. And all the drug shortages we've had too in the past four years or so, making it hard when we finally find a drug that works for patients, but that's a whole other story. It's on a subject of a future podcast.

Gavin: Cosopt Preservative-free was a big one for that. So that, I mean, we could add access as a barrier. So cost. Waste, affordability, and [00:19:00] access, paperwork for the physician are all barriers, so, you know, think The average ophthalmologist may not be as inclined to fill out special authority paperwork so that the patient can go from a generic to preservative free.

[00:19:15] First-Line Treatments for Glaucoma

Robert: So what's your approach now with the patient who's coming in with glaucoma as your initial therapy?

Gavin: I will tell them I feel preservative free is better for them. I'm upfront that there is a barrier in terms of it may not be covered. I tell them that if it was my eye, I would want preservative free because there's implications that there's potentially reduced rate of surgery, reduced side effects. Um, but that being said, I Let the patient know that there are covered options available that should lower the pressure, and that's been the standard of care for many years.

Robert: And I'm sure too, you, uh, propose, uh, SLT.

Gavin: Yes, sorry. Um, so I [00:20:00] usually tell them that there are A couple of first line options available, uh, as I mentioned that there's laser trabeculoplasty, which there's lots of great evidence as a first line treatment for glaucoma. And I'm, I feel like I try to push that first line, because why would you want to take a medication every day if you can have a laser that accomplishes the same thing and then compliance is taken out of the equation?

Uh, so, SLT is my preferred approach, but then if we are talking about drops, because some people for some reason may have a fear of laser or they've had it several times, uh, then I say, you know what, there are eye drops available. There are multiple classes. Our first line agents are usually I would consider a beta blocker, a prostaglandin first line, especially because, you know, You know, tomoptic XE you can use once a day dosing, and it generally doesn't have very many ocular side effects.

Um, but usually we want prostaglandins for efficacy in single dose. And then I'll mention, you know, [00:21:00] uh, latanoprostine bunode in terms of increased efficacy, relative affordability, but has a preservative, preservative free latanoprost. as the leading preservative option that's the most affordable and has the most evidence behind it.

And then, um, I will offer them a generic prostaglandin if coverage or affordability is a concern.

Robert: Yeah. little bit off topic, but since you dropped it in there, the latanoprostene bunod, um,

Gavin: I feel like if

Robert: brand name is Vyzulta. Yeah. Yeah.

Gavin: I feel like if they made a preservative free option and it was covered, that would be my go to. Because I do feel it's more efficacious, but I find some patients find it burns and has ocular side effects, so that sometimes is a limiting factor in terms of adherence or patients willing to stay on it. Um, [00:22:00] so I do find generic or preservative free latanoprost alone is often better tolerated, but I wonder if a preservative free version You might take that out of the equation.

Robert: And with air, it's the, it's the nitric oxide. Uh, of the molecule

Gavin: Yes, the nitric analog, um, is supposed to hopefully give another one to two points of, uh, millimeters of mercury lowering. And then, you know, from our core glaucoma trials, we know that every one millimeter of mercury is supposedly a 10 percent reduction in progression. So if you can get that for one drop.

Then, you know, I think that makes sense. And when vice will to first came out when you asked me to talk about it at tar provincial meeting, um, you know, it seemed like the go to then and now preservers have come on the field. And, you know, looking at the evidence, I do think there's an argument.

Preservative free or [00:23:00] sorry, preservative freeze come on the field. But I think there is an argument that preservative free is probably better long term for patients. But it's the question of access, affordability, and coverage for patients, which are issues at the moment. Because I think if there was coverage, and it was affordable for patients, and it didn't come in the little vials so everyone could use them, there would be less questions about it, I think.

[00:23:23] Surgical Considerations and Patient Experiences

Robert: Absolutely now do you have any I guess anecdotal experience from your practice since you're quite overloaded with surgery Patients who have been on preserved drops versus non preserved drops Do you feel you have enough information there from the patients you've seen on problems you have after surgery or around the time of surgery?

Gavin: Yeah, so, um, I do make an effort when they have a lot of signs of corneal toxicity or, you know, keratopathy, [00:24:00] I do make an effort to switch them prior to surgery. Uh, to be honest, it's probably not a long enough time course, but they often have high pressures and need surgery a little bit more urgently than I have time to work with with just managing their ocular surface.

So that's something I wish referring specialists might do a bit more, um, or referring optometrists. You know, manage the ocular surface, recognize the Preservative toxicity, because if you send a, an inflamed eye, your chances of success are, are lower. Um, so, yeah, I mean, I had one patient who came in and she was, you know, basically walked into the office in sunglasses and a wide brimmed hat, you know, on Zalcom's and Brinza, very red, inflamed eyes, glaucoma, not well controlled, pressures elevated, visual field progressing, uh, cataracts.

And we. We did [00:25:00] cataract with minimally invasive glaucoma surgery after switching her to preservative free. And even just switching her to preservative free, uh, she was so happy. She wasn't wearing sunglasses anymore, she felt like she could actually open her eyes, they weren't red and inflamed. So just that alone, I mean, we ended up doing surgery because of the cataracts and to try and get better control of her glaucoma, but Just switching to preservative free, and not everyone's going to be this dramatic, but for her, it made a huge difference in her life, and she was so much happier, and she was just, she thought she just had to live with these red, uncomfortable eyes for the rest of her life.

Robert: Yeah. Yeah, I would say just in my experience, patients just on long term glaucoma medications versus those who, haven't been on meds as long when it comes surgery. Uh, there's just, it's obvious from there being less bleeding at the time of surgery and easier to dissect the tissues [00:26:00] for, uh, when, when They haven't been on the drops for decades,

Gavin: Yes,

Robert: or not.

Gavin: the fresh conjunctiva. I don't see it too often,

Robert: No.

Gavin: but yeah, no. So I think, um, we didn't go into the studies, but basically, uh, eyes with preservative are often more likely to have kind of inflammatory mediators in the aqueous and in the conju, and they're more likely to scar down after filtering surgery. So I think our chances of surgical success and our ease of surgery is going to be greater if we, Um, it does take extra time, which is a limiting factor, and often another barrier we didn't mention is, you know, this is an extra, this is extra chair time.

It's writing extra prescriptions. You're writing for special authority from pharmacy, and then you're monitoring to see what their response is before surgery. So it's more time at the initial visit, [00:27:00] extra follow up, but all to try and get a better result with surgery. And that's why I said, I wish, I think we'll hopefully get there where people are aware of it more and done this prior to sending them to the glaucoma surgeon.

Robert: Do you tend to start patients on anti inflammatory drops before the surgery when you're worried that they have too much toxicity from their drops?

Gavin: If the eyes are super inflamed, I usually do, and, uh, oftentimes they'll come in with really high pressures. And, um, if it's both eyes, I'll make the switch knowing that the fellow eye is probably going to get the better benefit of the switch. And then I'll do a micropulse cyclophotocoagulation to get the pressures down, and then start their anti inflammatory drops from the micropulse, but keep them on it a bit longer, knowing that we're bridging the gap from, uh, cycloablation.

procedure to surgery. Um, I find the micropulse wears off, so I'm not too worried about inducing hypotony with a micropulse [00:28:00] followed by a glaucoma surgery.

[00:28:03] Conclusion and Final Thoughts

Robert: Anything else you want to bring up before we wrap things up?

Gavin: No, I think we covered a lot of it. Uh, so we talked about why we had preservatives in the first place and why we thought they were better, how that thought frame has Switched, and we now have an emerging paradigm that preservative free might be a better treatment alternative. We talked about how it may actually cause damage to the eye and worse outcomes later on.

Although they do lower the pressure initially, there's lots of evidence to show they work in that sense. Um, but it might actually be affecting our outcomes in terms of us having to do more surgery. And having worse results at the time of surgery by having patients on these medications.

Robert: Well, thanks for so much for being on the show.

Gavin: Oh, thank you very much for thinking of me, Rob. Appreciate it.

Robert: Okay. Take care. And, uh, go home. It's almost nine [00:29:00] o'clock at night here.

Gavin: Sounds good. Um, yeah. Missed you at CGS. Hope all is well on your end.

Robert: Yep. All good.

Gavin: Okay. Well, look forward to catching up with you when we get the next opportunity.

Robert: You betcha. Take care.

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