Aflibercept superior to PRP for Retinal Neovascularization in Diabetic Retinopathy: CLARITY Trial

Based on 7 fields and color stereoscopic fundus photographs, high-risk PDR is defined as moderate to severe NV (>1/4 to 1/3 disc diameter) of the disc (NVD), moderate NVD (<1/4 to 1/3 disc diameter), or moderate NV elsewhere (NVE) with vitreous or preretinal hemorrhage.

Panretinal photocoagulation (PRP) has been the criterion standard treatment for high-risk PDR for more than 40 years and, on an individual basis, is also used to treat low risk PDR and very severe nonproliferative diabetic retinopathy. Although the exact mechanism of PRP is unclear, destruction of areas of retinal capillary nonperfusion (CNP) is hypothesized to reduce the angiogenic drive from these areas. Repeated sessions of PRP may be required to cause regression of these new vessels, suggesting that some new vessels are more resistant to regression than others.

The Clinical Efficacy and Mechanistic Evaluation of Aflibercept for Proliferative Diabetic Retinopathy (CLARITY) trial, which was specifically designed to evaluate the efficacy of aflibercept (an antiVEGF therapy) vs PRP for persons with PDR without diabetic macular edema, showed that NV regresses rapidly with aflibercept and that subsequent withholding of treatment resulted in recurrence of NV in a proportion of eyes.

Similar to PRP, the patterns of regression of NV can vary. Approximately onefourth of eyes in the CLARITY trial continued to exhibit active NV during anti-VEGF treatment. Moreover, even in eyes in which NV was seen to have regressed, both reperfusion of the previously closed vessels or proliferation of NV de novo at another location in the retina were observed when treatment was withheld.

In this post hoc analysis, the researchers Sandra Halim and team described the regression patterns of NV by retinal location after treatment with either aflibercept or PRP in a subset of treatment-naive eyes with PDR at enrollment to better classify NV, understand treatment targets, and ultimately improve visual prognosis as published in JAMA Ophthalmology.

This post hoc analysis of the phase 2b randomized clinical single-masked multicenter noninferiority Clinical Efficacy and Mechanistic Evaluation of Aflibercept for Proliferative Diabetic Retinopathy (CLARITY) trial was conducted from November 1, 2019, to September 1, 2020, among 120 treatment-naive patients with proliferative diabetic retinopathy to evaluate the topography of NVD and NVE in 4 quadrants of the retina on color fundus photography at baseline and at 12 and 52 weeks after treatment.

In the CLARITY trial, patients were randomized to receive intravitreal aflibercept (2 mg/0.05 mL at baseline, 4 weeks, and 8 weeks, and as needed from 12 weeks onward) or PRP (completed in initial fractionated sessions and then on an as-needed basis when reviewed every 8 weeks).

Main outcomes were per-retinal quadrant frequencies of NV at baseline and frequencies of patterns of regression, recurrence, and new occurrence at 12-week and 52-week unmasked follow-up.

Results

• At baseline, NVD with or without NVE was observed in 42 eyes (35.0%), and NVE only was found in 78 eyes (65.0%); NVE had a predilection for the nasal quadrant [53.3%].

• Rates of regression with treatment were higher among eyes with NVE compared with eyes with NVD by 52 weeks, with NVD being more resistant to either treatment with higher rates of persistence than NVE. Considering NVE, the regression rate in the temporal quadrant was lowest.

• Eyes treated with aflibercept showed higher rates of regression of NVE compared with those treated with PRP but no difference was found for NVD.

• With respect to recurrence of NVE after regression, a lower proportion of eyes showed recurrence in the aflibercept group compared with the PRP group. This difference in pattern was associated with faster regression in the nasal quadrant with aflibercept than with PRP.

• Although aflibercept was superior to PRP for treating NVE, neither treatment was particularly effective against NVD by 52 weeks. This finding is clinically relevant because it emphasizes the importance of screening for NVD and classifying the severity of PDR, and severity has direct implications on treatment frequency and response.

• Key observations from the analysis include the finding that, at baseline, there was a higher proportion of eyes with NVE than NVD and that, during follow-up, there were more new occurrences of NVE than NVD.

• Furthermore, NVD was associated with more resistance to either PRP or anti-VEGF therapy compared with NVE.

• Regression of NVD occurred less frequently compared with regression of NVE, which was apparent at both week 12 and week 52. The proportion of eyes with persistent NVD (51.3%) despite treatment was nearly double that of eyes with persistent NVE (29.0%) at week 52.

• In terms of the topography of NVE at baseline, it was found that most eyes had NVE in the nasal quadrant (53.3%), followed by the superior (35.0%), temporal (28.3%), and inferior quadrants (19.2%)

The exact reason for rapid regression and less likelihood of NVE recurrence with aflibercept compared with PRP can only be hypothesized. It may be that the destruction of the peripheral retina by PRP to reduce VEGF production is indirect and takes time to become established, which is in contrast to the direct suppression of VEGF by aflibercept.

Alternatively, VEGF suppression by ablation of the peripheral retina may be insufficient to cause rapid regression of NV and is in accordance with clinical practice in which supplemental PRP is required to achieve the therapeutic threshold for continued VEGF suppression.

A further reason could be that aflibercept blocks all VEGF isoforms and the placental growth factor, and this may explain its added benefit compared with PRP. This possibility was substantiated by the results of Protocol T, in which the regression of NV was better achieved with aflibercept than other anti-VEGF agents. However, although aflibercept does not improve CNP, the main trigger for NV, it may stabilize progression of CNP.

The researchers concluded, "Our study further elaborates the results of the CLARITY trial, which showed that aflibercept is superior to PRP in that there are differences in the rate of regression, recurrence, persistence, and new occurrence between NVD and NVE and that neither treatment is particularly effective for NVD in the short term. We also observed variation in the aforementioned outcomes that were associated with both topography and treatment regimen."

This post hoc analysis found that NVD is less frequent but is associated with more resistance to currently available treatments than NVE. Aflibercept was superior to PRP for treating NVE, but neither treatment was particularly effective against NVD by 52 weeks. Future treatments are needed to better target NVD, which has poorer visual prognosis.

Source: Sandra Halim; Manjula Nugawela; Usha Chakravarthy et al JAMA Ophthalmol. 2021;139(5):501-507. doi:10.1001/jamaophthalmol.2021.0108