Lecture: Top Pearls from the DRCR Clinical Trials

Dr. Kitchens: I wanted to just thank you for having me give these talks here at the Mexican Retina Society meeting. I really hope, someday, that I can actually come to this meeting live and in person and give talks like this to you. But for the time being, because of COVID, I really just appreciate the opportunity to be able to give these different talks.

So the first talk that I’m going to be giving is the top five pearls from the DRCR clinical trials. And you’ll find that the DRCR pearls are deeper than just five separate pearls. So this actually is probably going to be more like 15 pearls.

These are my disclosures. And most importantly what I want to say is, is that I’m a participant in the DRCR network, and these are just my observations based off my experience over the last 15 years in the DRCR. But I am in no way speaking on behalf of the DRCR. And really we’re going to focus on three main things. All of which are going to help, hopefully, contribute to the way you manage patients clinically.

The first is going to be the role of manage of pharmacotherapy in the management of diabetic macular edema. And then towards the last 20% of the talk, we’re going to be talking about the use of Anti-VEGF therapy on diabetic retinopathy.

So just a little bit about the Diabetic Retinopathy Clinical Research network, or the DRCR. This is a group of practices across the United States, and even in Canada, that are looking at clinically important questions in regards to diabetic retinopathy. So basically this is our generation’s version of the ETDRS or the DRS. And so we have private practices, we have academic institutions, we have a variety of different places that are contributing to the DRCR involving over 1000 investigators. And so it really can have very meaningful and impactful answers to questions. We are here in Lexington, Kentucky.

And these are all of the different studies that the DRCR has participated in, up through December 2018. And they sequentially order their studies by letters. So the DRCR A Study, B Study, C Study, and so on. And we’re all the way down, actually now, to W and we’re starting to do double letters. So the AA Study and whatnot. Also, you have access to all of the slides I’m going to be showing you. The DRCR is very good about publishing online their presentations. And so I would encourage you to go online to the DRCR.net. You don’t have to be a member of the DRCR network to access these publications. And you can view and download the presentations.

So let’s get on with these pearls. I think the first pearl is relatively evident to everyone but it is that Anti-VEGF therapy is the gold standard for diabetic macular edema. We know this, courtesy of the DRCR Protocol I Study, which compared laser to ranibizumab, with either prompt or deferred laser. And compare that to triamcinolone plus prompt laser. We had great follow-through on these studies. And here we can see the overall outcome at one and two years.

In the top two lines, which showed a significant improvement in visual acuity that was sustained, are both the ranibizumab groups: prompt and deferred laser. The yellow graph is actually triamcinolone plus prompt laser. And the purple graph is actually the laser treatment group alone. And so this, really for the first time, established that Anti-VEGF therapy was the gold standard for the treatment of diabetic macular edema.

And when we actually looked at different factors, other factors really didn’t play a role. So if you look at the baseline visual acuity. Both patients with good visual acuity and poor visual acuity, Anti-VEGF therapy was the gold standard. When you look at patients who had a thicker OCT versus a thinner OCT, once again we saw Anti-VEGF therapy was better than triamcinolone and prompt laser or laser alone.

When we look at change in visual acuity, or prior diabetic macular edema treatment, those patients who had prior treatment. They did just as well up as the patients who had no treatment or were treatment naive. When you look at the type of macular edema, focal edema versus diffuse edema, versus neither, you can see Anti-VEGF therapy did well across the board.

And I’ll point out particularly here, focal edema. I remember back before the data of the study was known, we used to treat focal edema with focal laser treatment, and then more diffuse edema with triamcinolone or Anti-VEGF therapy. A patient’s level of retinopathy really didn’t discern whether or not they responded better to Anti-VEGF therapy versus other therapies. So once again, the blue and the orange lines being Anti-VEGF therapy, did better than everything else.

There was one exception, however. And that exception was in pseudophakic patients. And so when you look at the pseudophakic patients, actually, we can see that triamcinolone and prompt laser treatment actually did do as well as Anti-VEGF therapy. We will come back to this in just a bit, so hold that thought.

We also saw that Anti-VEGF therapy had a really long-lasting effect on DME in a positive way. So these visual acuity improvements that we saw at one and two years were maintained throughout five years of the study. And what is very interesting is, is that the number of injections actually went down over that study. So in other words, in the first year patients, on average, would receive eight or nine injections in the ranibizumab treatment groups. The second year it’d be five or six, the third year it’d be three or four, and by years four and five, it was just one or two injections given.

So there is something about Anti-VEGF therapy in the setting of DME, that for the average patient actually shows a significant change in the way their retinopathy responds and their diabetic macular edema responds to treatment.

The second pearl is, is that there does appear to be a difference between Anti-VEGF therapies. Years after the Protocol I Study, we now had three FDA-approved treatments for diabetic macular edema. And this led the DRCR network to study and compare these three treatments in the DRCR Protocol T Study. Where we compare two milligrams of intravitreal aflibercept, versus 1.25 milligrams of intravitreal bevacizumab, and 0.3 milligrams of intravitreal ranibizumab.

Now I know for those of you who are international, the 0.3 milligram dose of intravitreal ranibizumab is actually different than what we see outside the U.S. In the U.S., 0.3 is the FDA-approved treatment for diabetic macular edema. Everywhere else it’s the 0.5 milligram dose. Now when you compare the statistics in this study to the outcomes in the Protocol I Study where the 0.5 milligram dose was used, you can see that they are very similar. So I think we can extrapolate the 0.5 and 0.3 being fairly equivalent. That holds true also for the RIDE and RISE Studies where they compared 0.3 and 0.5.

Very equally matched baseline characteristics, including prior treatments with Anti-VEGF therapy, And we look at the entire study population, we can see that there is a slight improvement with aflibercept compared to ranibizumab and bevacizumab. When we see OCT, similarly we see a greater drying effect with aflibercept versus ranibizumab and bevacizumab. But when you break these study populations out to those patients who were 20/50 or worse, compared to the patients with good visual acuity, we can see that aflibercept actually does better. Almost a line better compared to ranibizumab at one year. And almost two lines of visual acuity better compared to bevacizumab.

And this has actually led to insurance companies in the United States allowing us to use aflibercept sooner in these patients with worse visual acuity. And the OCT differences are actually greater in those patients that are 20/50 or worse, as far as the drying effect is concerned.

Now I would be remiss if I did not point out the fact that there is a big cost difference. And here we can see the differences in cost between aflibercept, bevacizumab, and ranibizumab in the Protocol T Study.

Now, steroids may still have a role in managing diabetic macular edema. You will remember this from the Protocol I Study, as I pointed out earlier, that there actually was good equivalents when comparing ranibizumab with prompt or deferred laser to triamcinolone and prompt laser, in pseudophakic patients. And when we simply stratify out the pseudophakic patients, we can actually see that the yellow line now approximates what we see in the patients that were treated with Anti-VEGF therapy. And the reason is, is because those patients treated with triamcinolone and prompt laser, develop cataracts if they were phakic. And that led to decreased visual acuity at one year and two years. So if we have pseudophakic patients at baseline, steroids seem to be of similar efficacy. But with far fewer treatments.

And here we can see the median number of injections during year one and two, and where we’re giving nine or ten injections in Protocol I of Anti-VEGF therapy in year one. It’s only three of triamcinolone plus laser. When we look at the Protocol T Study, we can see that there are a fair number of patients that have persistent diabetic macular edema with reduced vision. And this includes patients treated with aflibercept, bevacizumab, and ranibizumab.

Now the DRCR actually looked at combining ranibizumab with the dexamethasone or ozurdex implant, in a study called the DRCR Protocol U Study. And in the Protocol U Study, they compared patients who were run-in with ranibizumab and then randomized to either quarterly injections or every three month injections of ozurdex and ranibizumab versus ranibizumab alone. We really didn’t see any significant difference in patients visual acuity outcomes as it pertains to the entire group. But the pseudophakic patients, again in the combination group treated with dexamethasone and ranibizumab, actually showed a pretty significant difference. Whereas the phakic patients who might well have developed a cataract during those first six months, actually showed a difference in favor of ranibizumab.

But when we look at OCTs, we can see that there is a greater drying effect in the combination treatment group of about 50 microns. And so this is fairly significant. So for those patients who have significant, persistent edema, there may still be a role for steroids. Although steroids have side effects, and we can see these. Mainly cataracts and elevated intraocular pressure. This once again, points to the fact that fewer Anti-VEGF injections are needed over time, so perhaps as we go on and on with therapy, we actually may not require as many injections. And so this may also play a role in determining what you want to use.

So what about those non responders? Maybe they don’t need steroids? As I just showed, fewer injections over time, but there are still a fair number of patients who have persistent edema. On the order of about 40% of patients in the Protocol I Study that were treated ranibizumab, still had central-involved edema through their six month visit.

How did these patients do over time? Well, we can see that there are still a fair number, 40% after three years of therapy, that will have persistent edema. But those patients with persistent edema don’t do so poorly. We can see 20/25 if they have no persistent edema and 20/32 on average at three if they have persistent edema. But they are at a greater risk of vision loss. So we can see here that there is, by year two and three, a pretty significant amount compared to the patients that do not have persistent edema. However, still well less than 20%.

And this persistent edema story holds true across the board with all Anti-VEGF therapies. So we can see that there are patients who have persistent edema out to six months when treated with aflibercept, bevacizumab, ir ranibizumab. But if you stick with it, many of these patients with persistent edema will actually have significant visual acuity gains through year two.

What about the patient with good vision and diabetic macular edema? Well, if you look at those patients and we did in the Protocol V Study. These are patients with good visual acuity. We can see that there is a lower likelihood of these patients having significant vision loss at two years, in all the groups.

So how do we judge this? Well, first of all, you can say you can do nothing. And if you look here at the patients who had observation, many of these patients did very well. With 74% of the patients treated with laser and 63% of the patients treated with observation or only observed, actually did not need any treatments throughout the two years of the study.

Or you could say inject. And if you look at inject you can say that the chances of you having 20/20 or better vision at two years, is actually greater in those patients treated with aflibercept. But there is a cost and that cost is about 8 injections over those two years, on average.

And finally, you could say, “Look, I like to laser.” And laser shows that there’s a decreased need for treatment over those first two years if you do focal laser treatment in the setting of diabetic macular edema.

Finally, as we come to a close here. The role of Anti-VEGF therapy and diabetic retinopathy is really being expounded upon over the last couple of years. We know that Anti-VEGF therapy is effective in prolific diabetic retinopathy. This is from the Protocol S Study, which compared Anti-VEGF therapy to PRP laser treatment. And we can see significantly lower numbers of vitrectomy in the patients treated with Anti-VEGF therapy versus laser treatment. And lower rates of other complications associated with this. Even out to five years where the amount of vitrectomies performed was about half in the Anti-VEGF group versus PDR. However, there’s a cost and that cost is injections. 20 injections over five years versus 5.4 in the PRP group.

But with this Anti-VEGF therapy, we see significant improvement in diabetic retinopathy. Upwards of about 50% in the Protocol S Study had a two step improvement in retinopathy severity score. In addition, we see visual acuity improvements in these patients, even the patients without diabetic macular edema, we can still see a significant improvement. And for those patients with diabetic macular edema, we see even greater improvements. And the Anti-VEGF therapy actually reduces the occurrence of diabetic macular edema.

Importantly, Anti-VEGF therapy does not cause traction to progress, which is really important in treating these patients who might have early traction. So there’s lower chance of needing to go to surgery with what we consider the crunch phenomenon that used to happen, compared to previous. And there’s less visual field loss with Anti-VEGF therapy over the first two years. But interestingly, as we go out to five years we can see that there is some peripheral visual field loss, even in patients who were treated only with Anti-VEGF therapy. And this indicates that the ischemia still progresses.

Now what Anti-VEGF therapy does not appear to do, is it doesn’t appear to clear vitreous hemorrhage. And the Protocol N Study compared a saline injection to a ranibizumab injection. And you can see the probability of going on and need vitrectomy is about the same between the two groups, in the early follow up and the late follow up periods.

So we can safely say that it looks like Anti-VEGF therapy doesn’t help to clear vitreous hemorrhage, but what does do is reduce the recurrence of vitreous hemorrhage.

Finally, in the Protocol S Study, we do have some indication that pattern laser treatment may not be as effective as what we see with single-spot PRP. And we can see that, actually, there were more patients that actually went on to develop a proliferative disease, or worsening PDR in these patients treated with proliferative disease. And this actually led the DRCR to make a statement that pattern laser may not be as effective.

So in summary, the big pearls to take home from this talk is that Anti-VEGF therapy is the standard of care for DME. The number of injections do tend to decrease over time. There is an efficacy difference in Anti-VEGF therapies for patients with lower vision. And there’s a large cost difference between these therapies. Using Anti-VEGF therapy for DME is effective, even in under responsive therapies, under responsive patients, if you stick with it. And steroids still may have a role in those pseudophakic patients. And that Anti-VEGF therapy is non-inferior to PRP and PDR.

Thank you, again, and I apologize for going over just a bit. I appreciate you having me and everyone stay healthy.