Early Use of VEGF Inhibitors Can Prevent "Leaving Vision on the Table"

How aggressively should patients with diabetic macular edema be treated? And what is the right treatment? An ophthalmologist and a retina specialist say, for some patients, early use of a new class of therapy, the vascular endothelial growth factor (VEGF) inhibitors, could make the difference in preventing vision loss—and even reversing diabetic retinopathy.

The value of anti-VEGF therapy has been demonstrated in clinical trials, according to experts who took part in a Peer Exchange, “Diabetes-Related Complications: A Focus on Diabetic Macular Edema,” convened earlier this year by The American Journal of Managed Care.

Taking part in the discussion were John W. Kitchens, MD, a vitreoretinal surgeon at Retina Associates of Kentucky; Rishi P. Singh, MD, staff physician at the Cleveland Clinic and assistant professor of ophthalmology at Case Western Reserve University; Steven Peskin, MD, MBA, FACP, executive medical director of Population Health for Horizon Healthcare Innovations of New Jersey; and moderator, Peter Salgo, MD, associate director of Surgical Intensive Care at New York-Presbyterian Hospital.

Who Makes Up the Eye Care Team?

The early discussion revealed a troubling fact: despite recommendations that patients with diabetes be screened annually for ocular conditions, only about 50% of them are evaluated on schedule. Salgo returned to this point repeatedly, asking what could be done to raise that percentage, which Singh said is actually higher in managed care settings—and better than it once was. Optometrists—who are not medical doctors—may do some routine screenings, with other examination done by ophthalmologists.

If a problem is found, the patient might see a retina specialist, a rarer subspecialty that Kitchens said focuses on macular degeneration, diabetic retinopathy, and vein occlusions. Once patients have center-involved DME, Kitchens said, “those patients really do better with retina specialists.”

The order of treatment matters, Kitchens and Singh agreed. Years ago, laser treatments were the standard of care for DME, but that no longer holds—and using laser treatments first may even limit the effectiveness of VEGF inhibitors. This sea change has created new practice patterns, Kitchens and Singh said, with retina specialists consulting with ophthalmology practices from afar, or setting up multiple offices and traveling to where the patients are.

< Peskin agreed, saying that asking someone to travel 25 miles in New Jersey might take more than an hour; this won’t work for patients who tend to be older with other health problems. Singh said specialists may even fly in to see patients. “That’s pretty much a commonality in our field now,” he said.

The team-based approach is becoming the norm in diabetes care, according to the panelists. Peskin discussed how new reimbursement models, such as bundled payments, are rewarding those “high-performing practices” that use diabetes educators, even if this group does not bill directly. Peskin praised members of the American Association of Diabetes Educators as “very passionate and very engaged in the process.”

Why Early Intervention Matters

“We know that 95% of vision loss from diabetic retinopathy is preventable or treatable,” Kitchens said. While early intervention may appear to cost more up front, this can “negate some of the cost advantages or disadvantages of certain medications,” he said.

Using anti-VEGF therapy up front is cost-effective, Kitchens said, because there’s a greater chance of preserving vision than waiting for laser treatments to fail. Singh cited a randomized, placebo-controlled crossover study that showed patients who waited a year for anti-VEGF therapy could not gain as much visual acuity. “We know that the cut point is at least 1 year, and probably earlier than that,” he said. “It has been shown in the past few years, and in a few studies, that laser is not the standard of care for this treatment anymore,” Singh added.

What are the barriers to screening more people with diabetes? Singh said major professional societies have not endorsed newer imaging technologies that could cut time from the process, and many patients don’t want to miss an afternoon of work for dilation. “It takes people out 3 to 4 hours necessarily for that process,” he said.

A change in protocols and payer policies could revolutionize screening, putting tools in convenient places like pharmacies and getting patients into care earlier. Peskin was candid that socioeconomic factors and payer policies can slow the process. Singh said Medicare—which funds most of the affected population&mdash;needs to pay for more preventive care.

The Affordable Care Act (ACA) has given more patients coverage, but the list of preventive services that are fully covered leaves gaps. Along with that, Kitchens said, patient education matters. “Even if you get the services covered, you’ve got to get the patients engaged into going to get the exam.” Today, he said, treatments exist that can “dramatically improve patients’ visual acuity, reduce not only

diabetic macular edema [but] also reverse retinopathy. When physicians and patients understand that, they’re much more engaged and interested in going to see somebody.”

VEGF Inhibitors Now First-Line Therapy

Until recently, first-line treatment for DME involved laser photocoagulation. Other options were intraocular steroids and, for the most severe cases, surgery. Today, anti-VEGF therapy has changed the order: the therapy is considered first-line treatment, Singh said. VEGF inhibitors are given by injection, according to protocols that vary depending on which version is used. Kitchens discussed 2 important studies, by the Diabetic Retinopathy Clinical Research (DRCR) Network, that showed,

1. VEGF inhibitors were better than other options

2. Patients with more serious vision loss when treatment begins will benefit from the 2 anti-VEGF therapies developed specifically for ocular conditions, rather than a much cheaper version used off label.

DRCR Protocol I Study. Kitchens discussed results that compared improvements in visual acuity after treatment with the VEGF inhibitor ranibizumab (Lucentis) or the steroid, triamcinolone, with laser treatment. Reported in Ophthalmology in 2010, these results showed that the VEGF inhibitor should be considered for patients with DME.¹ In 2012, a follow-up study found that, based on the amount of vision restored, the cost of treating these patients with the VEGF inhibitor could be justified by the Veterans’ Administration.² By the 3-year mark, results showed that for some patients, starting ranibizumab with deferring laser treatment “is no better, and possibly worse,” than starting with the VEGF inhibitor and deferring laser treatment.³

Singh said an important cross-over study comparing patients who had laser treatment alone versus VEGF therapy for a year found that those who had laser-only first didn’t gain as much visual acuity if they later began using ranibizumab.⁴ “So we know the cut point is at least one year, and probably earlier than that,” he said. “That was really a sea change for what we do,” Kitchens said. “Almost everyone now starts with anti-VEFG therapy.” Because vision was improving, patients had as many as 9 injections the first year, but, over time, they had fewer injections per year, he said. Salgo asked if this meant the therapy was “turning the disease process off.” “Not just the macular edema, but also the diabetic retinopathy,” Kitchens said. The patients with nonproliferative retinopathy often saw many degrees of improvement. “So you’re taking the worst of the worst and pulling them out of the fire,” he said. Said Singh, “It’s all brand new.”

Will Payers Fund New Anti-VEGF Therapies?

Asked if payers are willing to fund anti-VEGF therapy, Peskin said, “We certainly do pay for these therapies; where the rubber meets the road sometimes is the amount of treatment or the treatment options.”

The discovery that bevacizumab (Avastin), an anti-VEGF treatment often used in colorectal, lung, and ovarian cancer, could be repackaged off-label and have some effect on DME made payers want to force eye specialists to try this treatment first. After all, the price difference was huge—$50 a dose for bevacizumab compared with up to $2000 for alternatives.⁵ But another study by the DRCR showed that not all VEGF therapies are the same.

DRCR Protocol T. This study compared bevacizumab with ranibizumab and a newer anti-VEGF therapy, aflibercept (Eylea), in a head-to-head trial.6 As Kitchens discussed, patients who started with better vision, up to about 20/40 in the eye, “did equally well with all the medicines.” But for patients starting with more impaired vision, 20/50 or worse, Kitchens said, “they actually did better with one of the other anti-VEGF medicines, not by a little but by a lot.” (Results showed that patients starting with 20/50 vision or worse who were treated with the newer medication, flibercept, did best of all.6) When payers insist that even those with more impaired vision must start with bevacizumab, Kitchens said, “that’s where we run into trouble.” Eye specialists are told to wait until treatment fails, “and that definition of failure paints us into a corner.”

But given the price difference, is it wrong to tell physicians what to use? Singh said it’s important to pay attention to the “art” of medicine, which is what led to the discovery of the off-label option in the first place. When a more expensive therapy is desired, his practice works with payers and makes sure preauthorizations are in place, well in advance, so there are no surprises. Peskin said medical directors are willing to take phone calls and have a discussion based on new evidence, but Kitchens said many eye specialists won’t try. Thus, the challenge of DME is getting patients screened, identifying those who need treatment, and picking the right treatment. “If you don’t treat these patients early, you’re leaving vision on the table,” Kitchens said.

The Road Ahead in DME and Diabetes Care

New payment models and incentives for providing the best care, Peskin said, represent a “seismic” change. “We want to see that quality is preserved so that we don’t have amputations, so that we don’t have people that end up blind, so that we don’t have people that end up on dialysis,” he said. While Horizon has not tried bundled payments in eye care, he said, “but I’m sure we will.”

Salgo kept returning to the 50% who aren’t being screened. “I think a lot of it’s related to diabetes education,” Singh said. “We have to come up with more efficient screening methods,” and new locations, he said. “We’re taking the care to where the populations are, rather than having people go to the eye retailer,” Peskin said. The ACA has expanded coverage and offers some new options, but Kitchens said change will take time: “You can’t really turn the Titanic around overnight.” References

1. Elman MJ, Aiello LP, Beck RW, et al. Diabetic Retinopathy Clinical Research Network: Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus laser for diabetic macular edema. Ophthalmology. 2010;117(6):1064-1077.e35. doi: 10.1016/j.ophtha.2010.02.031.

2. Dewan V, Lambert D, Edler J, Kymes S, Apte RS. Cost-effectiveness analysis of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2012;119(8):1679-1684. doi: 10.1016/j.optha.2012.01.049.

3. Elman MJ, Qin H, Aiello LP, et al. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: three-year randomized trial results. Ophthalmology. 2012;119(11):2312-2318. doi: 10.1016/j.ophtha.2012.08.022.

4. Brown DM, Nguyen QD, Marcus DM, et al. Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from 2 phase III trials: RISE and RIDE. Ophthalmology. 2013;120(10):2013-2022. doi: 10.1016/j.ophtha.2013.02.034.

5. Caffrey MK. NEJM Study: Aflibercept offers benefits over rivals for DME if vision loss is worse at outset. Am J Manag Care. 2015;21(SP11):SP370.

6. The Diabetic Retinopathy Clinical Network: Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372(13):1193-1203. doi: 10.1056/NEJMoa1414264.

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