Treatment for PDR

More data needed for anti VEGF treatments in high-risk proliferative diabetic retinopathy patients

Dermot McGrath

Posted: Thursday, November 1, 2018

Persistent and stable new vessels following PRP.
The retinopathy is not biochemically active.
More laser will not cause complete regression

While the use of anti-VEGF injections offers exciting possibilities for the treatment of proliferative diabetic retinopathy (PDR), it is still too early to determine the extent to which they will change current clinical practice, according to Alistair Laidlaw, MD FRCS FRCOphth.

“The anti-VEGF drugs are very promising but the evidence so far is in low-risk groups. We really don’t know how effective these treatments are in high-risk categories. The drugs are very expensive compared to laser treatments and the patients need intensive follow-up.

“We also don’t know about long-term effect and whether anti-VEGF succeeds in switching off the disease forever or just delaying its progression,” he told delegates attending the 8th EURETINA Winter Meeting in Budapest.

In an overview of the pathophysiology and treatment options for PDR, Dr Laidlaw, Consultant Ophthalmic Surgeon at St Thomas’ Hospital London, United Kingdom, said that the role of the vitreous in the disease process should not be underestimated.

“One of the take-home messages today is that PDR is actually a misnomer and should more properly be called proliferative diabetic vitreo-retinopathy (PDVR). As part of the disease process, the vitreous itself is affected with alterations in vitreous collagen, fibronectin-induced vitreoretinal adhesion and vitreous liquefaction. The vitreous shrinks with vitreoschisis and patchy retinal adhesion, which then pulls tangentially on the retina. It is a biochemical process leading to a mechanical effect. It is the vitreous traction on the retina or retinal new vessels that causes the vision loss,” he said.

Non-PDR is clinically measured by examination of the retina, applying the 4-2-1 rule, said Dr Laidlaw: 4 quadrants with blot haemorrhages, 2 quadrants with venous beading and 1 quadrant with intraretinal microvascular abnormality (IRMA). Severe disease is the presence of one out of the three criteria, very severe two out of three, and aggravated very severe equates to all three of these criteria being present. “If a patient has severe NPDR, then they have a 17% chance of developing high-risk characteristics of PDR within the next year and are at risk of vision loss from PDR,” he said.

If new vessels are present they can be divided into high-risk or low-risk PDR. High-risk characteristics are new vessels at the disc of more than a third of disc area, new vessels less than this size with a pre-retinal or vitreous haemorrhage or new vessels elsewhere with a pre-retinal or vitreous haemorrhage. Low-risk PDR involves new vessels that do not meet those criteria.

Panretinal laser photocoagulation (PRP) remains the standard treatment for PDR, noted Dr Laidlaw, highlighting the results of the landmark Diabetic Retinopathy Study, which found that patients who received PRP had significantly better results than those who received no treatment. PRP reduced the risk of severe visual loss by more than 50%. Untreated eyes had a vision loss rate of 16.3%, whereas treated eyes only had a vision loss rate of 6.4% over two years.

“High-risk characteristics used to be the threshold for application of panretinal laser,” said Dr Laidlaw. “The reason why there has been mission creep in terms of performing laser earlier is that the 48-month results were not just clearly in favour of treatment for the high-risk patients but also for those with low-risk PDR. The risk of severe vision loss was 9% for PRP-treated eyes compared to about 17% for observation. That is a big difference, particularly when one considers the difficulty many of us have with getting these patients to come back regularly,” he said. It is for this reason that many doctors have been applying PRP in patients with low-risk characteristics or severe non-PDR.

Looking at the clinical trial data for anti-VEGF treatments, Dr Laidlaw said that the evidence from both the Protocol S and the UK-based CLARITY trials herald a potentially promising new era in pharmacological treatments for PDR. It should be noted, however, that around half of the patients in each study did not have high-risk PDR. This means that the short-term risk of sight loss in each study was not that high. It also means that there are few data on the effect of anti-VEGF injections in patients with very extensive new vessels: such patients may be at risk of developing tractional complications from anti-VEGF therapy.

Protocol S, which compared the efficacy of prompt PRP to 0.5mg ranibizumab with deferred PRP, demonstrated that the visual acuity outcomes at two years were at least equivalent in both groups, with the mean change in visual acuity in the ranibizumab group demonstrating non-inferiority, and area under the curve analysis demonstrating superiority of the ranibizumab group. Decreased incidence of vitrectomy was also seen in this group. Protocol S included patients with diabetic macular oedema.

In the CLARITY trial, patients with PDR who were treated with intravitreal aflibercept had an improved outcome at one year compared with those treated with PRP. A significant proportion of eyes showed total regression of retinal new vessels in the aflibercept group, said Dr Laidlaw.

These first trials are very encouraging; however, anti-VEGF injecitons are expensive and not without risk; there may also be a greater burden of follow-up visits for patients undergoing injection therapy for PDR and there are only short-term results so far.

Alistair Laidlaw: