Key Findings of DRCR Protocol AC Study


Experts discuss the recent DRCR Protocol AC study comparing aflibercept monotherapy vs bevacizumab first therapy for patients with diabetic macular edema (DME).


Ehsan Rahimy, MD: More recently, we’ve had the DRCR [Diabetic Retinopathy Clinical Research Network] Protocol AC, which has generated a lot of discussion. This paper was published in the New England Journal of Medicine, it studied the efficacy of administering aflibercept monotherapy compared with a bevacizumab-first approach, essentially emulating step therapy. Jon, can you take us into the study? What was the rationale here?

Jonathan Jonisch, MD: I don’t know the exact rationale, but I can tell you what most likely was the rationale of this study because it is an interesting study. But the idea is, in many patients, we know aflibercept is a superior drug. But if we start everyone on bevacizumab and obviously have the significant cost savings attached to that with each injection, are patients any worse off getting rescue therapy with aflibercept than patients who are just blanketed with everyone’s going to be on aflibercept because it may be a better drug and the costs are appropriate. I think that was the basic question, are we harming patients? Are patients going to do worse starting on bevacizumab like a lot of our step edits mandate; are they going to do worse?

The crux of this study came down to, again, they’re trying to mimic what we do in the clinic, and they created a retreatment algorithm. I have it written down here. In order to be switched from bevacizumab to aflibercept, the patients had to have all 4: a persistent center-involved DME [diabetic macular edema], recent treatment in the eye, no recent improvement in the eye condition, and suboptimal vision. If all 4 of those are met, the patient was switched over. I don’t know, I’ve never spoken to any of my mentors or my colleagues I speak with in our community who treat anywhere near that kind of regimen. I’m not sure how that was created, but I think at the very least, you can call it very rigid. Many of us would just need persistent DME, especially with some vision change, to switch. Despite that rigid retreatment criteria, over three-quarters of the patients ended up over the 2 years being switched to aflibercept.

So the take home points are kind of a double-edged sword. The top line data say that patients who started on bevacizumab had the same visual acuity as the patients who were started on aflibercept. That’s one hand showing the benefit and supporting some of these step therapies as a reasonable first-line approach. The counter to that is that over three-quarters of the patients failed initial therapy. Is it reasonable to make a patient start a treatment for which their success rate is going to be less than 25% in terms of maintaining that? It created a lot of questions in my mind, more than it answered. But again, you could take home the point that there is reassurance that we’re not significantly harming our patients in this 2-year time frame [when starting] with the bevacizumab first.

Ehsan Rahimy, MD: Veeral, I think I had spoken with you about this before and you made a really nice point about [how] you could approach arguing the study from multiple angles. Do you think you can touch on that? You told me about that before.

Veeral Sheth, MD, MBA, FASRS, FACS: Well, there’s the provider angle, where you’re thinking, “I can feel confident that I can start them on whatever I need to and switch them whenever I need to.” That the problem is, as a patient, I would feel like maybe we’re playing with fire a bit. I think we’ve all had patients where [when] they don’t do well, we want to switch them right away. We know that if you don’t switch them, you’re on the clock. The more this pathology builds up and lingers in the eye, the worst patients are going to do in the end, despite what we see in the data here.

The other thing is, we want to make sure we maintain some degree of choice. We’re already kind of fighting back against some of the mandates by insurance companies. Out of context, this trial becomes a bit difficult for us because payers can take this and say, “Everybody start with this,” and it starts to eliminate choice. I think we’ve got to be careful with how we look at these data. I think Jon hit it on the head, there are different ways you can look at this, good and bad. I guess it’s reassuring that these patients did well, but I think in that process and in this protocol and with this retreatment criteria, you’re gambling a bit, and it makes me feel a little uncomfortable thinking about it.

Transcript edited for clarity.

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