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08-22-2017 | Retinopathy | Editorial | Article

Antivascular endothelial growth factor treatment for proliferative diabetic retinopathy: Perspective on the CLARITY study

Nathaniel B. Rieveschl, Felipe F. Conti, Rishi P. Singh

Current standard of care treatment for proliferative diabetic retinopathy

Diabetic retinopathy is a frequently encountered complication in the diabetic population. About 40% of patients with diabetes over 40 years of age are estimated to have some degree of retinopathy [1]. Roughly half of all eyes with proliferative diabetic retinopathy (PDR) will have significant vision loss if left untreated [2]. PDR is caused by retinal ischemia and the resultant production of angiogenic factors such as vascular endothelial growth factor (VEGF). Panretinal photocoagulation (PRP) is the current standard of care treatment for PDR. PDR works by destroying the local ischemic photoreceptors and retinal pigment epithelium and, by that, it decreases the release of angiogenic factors thereby reducing stimuli for neovascularization. PRP reduces the risk of substantial vision loss from PDR by 50% or more, with the benefit being most significant in eyes with high-risk PDR [3]. However, PRP can damage the retina, leading to several visual side effects.

New treatment perspective

The advent of intravitreal anti-VEGF drugs has presented a fresh approach to PDR treatment, particularly in eyes with concomitant diabetic macular edema (DME). Options for anti-VEGF treatment include the US Food and Drug Administration-approved regimens of ranibizumab or aflibercept or the off-label usage of bevacizumab. Recent data utilizing these agents for PDR have been released and this article summarizes the findings of these studies and the key differences noted between treatment groups.

The Protocol S study evaluated intravitreal ranibizumab injection (IRI) compared with PRP treatment for PDR [4]. If ranibizumab treatment failed, PRP was permitted. After 2 years of treatment, the mean best corrected visual acuity (BCVA) improved by 2.8 letters in the ranibizumab group and by 0.2 letters in the PRP group. The mean change in BCVA between the PRP and ranibizumab groups favored ranibizumab by 3.0 letters in eyes with DME at baseline and by 1.4 letters in eyes without DME at baseline. Both groups had similar proportions of patients with 15 or more letters of improvement or loss. In the ranibizumab group, the median number of IRIs received by eyes without DME at baseline was seven in the first year and three in the second year. In eyes with baseline DME, a median of nine IRIs were administered over the first year and five in the second year. In the ranibizumab group, 6% of eyes also received PRP. Of eyes in the control group, 45% received additional PRP beyond the initial treatment.

More recently, the CLARITY study compared intravitreal aflibercept injection (IAI) to standard PRP treatment for PDR [5]. Since DME could be a bias for measuring visual acuity results, eyes with macular edema were excluded as opposed to the Protocol S study. Through 52 weeks of treatment, the mean BCVA in the PRP group decreased by 3.0 letters from baseline while the aflibercept group improved by 1.1 letters. The aflibercept group also had more patients with 10 or more letters of improvement and fewer patients with 10 or more letter loss compared with the control group. The mean total number of IAIs received by the aflibercept group was 4.4, and only two patients in this group required supplemental PRP. Patients in the PRP group received from one to seven laser sessions in the first 12 weeks, with most eyes requiring between one and four sessions.

The results of CLARITY and Protocol S showed that anti-VEGF treatment can prevent significant visual loss as effectively as PRP over a period of 2 years, even reaching superior visual outcomes than with laser therapy. The most important finding of these studies is that, while the outcomes of PDR appear comparable, there were significantly fewer injections given in the CLARITY study using aflibercept versus the Protocol S utilizing ranibizumab (4.4 versus 7.0 injections, respectively). This might represent the differences in binding affinity, targets, and inhibition of other factors beyond VEGF between these anti-VEGF drugs. It is also important to note that the better BCVA change in PRP group in Protocol S may be due to the fact that patients in the PRP group were allowed to have ranibizumab to treat DME, unlike in CLARITY. Figure 1 and Table 1 summarize the results of the two studies.

Figure 1. Mean change in visual acuity in both studies.

Table 1. Comparison of the CLARITY and Protocol S studies [click to expand].

Comparison between treatment strategies

Both trials showed that PRP and intravitreal anti-VEGF injections have similarly low rates of serious adverse events. Protocol S reported a 0.5% incidence of injection-related endophthalmitis in the ranibizumab group. However, the incidence of ocular inflammation excluding endophthalmitis was greater in the PRP group than in the ranibizumab group (4 vs 1%, respectively). Tractional retinal detachment (TRD) in PDR may occur or progress after intravitreal anti-VEGF [6], while the incidence rate of TRD with PRP is extremely low [2]. Additionally, CLARITY reported a significantly higher incidence of new or increasing vitreous hemorrhage in the PRP compared with the aflibercept group (18 vs 9%, respectively; p=0.034). Even though both studies did not report serious arterial thromboembolic events, it is important to keep in mind that all anti-VEGF drugs can decrease the plasma free-VEGF levels, possibly increasing the risk of myocardial infarction or cerebrovascular accident in high-risk patients [7]; PRP avoids any potential systemic exposure to VEGF blockade. Patients with PDR receiving PRP are more likely to experience peripheral visual field loss, night blindness, exacerbation of macular edema, and color vision changes due to the destruction of retinal tissue inherent to the procedure.

Though intravitreal anti-VEGF drugs have presented a promising therapy option for PDR patients, treatment burden still represents a disparity between them since PRP costs are significantly lower and treatment can be completed in fewer sessions. PRP can be performed as an outpatient procedure and is completed in one or more visits (depending on the patient’s tolerance for the discomfort of the procedure, although anesthesia may be used), while intravitreal anti-VEGF must be injected several times per year. In addition, laser treatment has longer lasting effects and requires fewer follow-up visits than with anti-VEGF drugs. We still lack a large randomized study utilizing bevacizumab for this same indication, which might provide better insights on whether a lower-cost drug might provide similar outcomes.


The results of these studies indicate that anti-VEGF agents are a very efficacious and promising alternative treatment to PRP for PDR with or without DME. While cross-trial comparisons are difficult, there does appear to be a difference in the dosing frequency noted between these drugs that favors aflibercept [8]. However, the long-term efficacy of intravitreal anti-VEGF agents for the treatment of PDR remains undetermined and requires further ongoing investigation.


The authors do not have any relationships to disclose.

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