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UPFRONT: Rethinking Treatment Choice for Proliferative Diabetic Retinopathy

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In the early 1970s, the landmark Diabetic Retinopathy Study (DRS) was conducted by the National Eye Institute (NEI) to evaluate the safety and efficacy of panretinal photocoagulation (PRP) in advanced diabetic retinopathy (DR). In the study, 1,758 patients with either proliferative diabetic retinopathy (PDR) in one eye or severe nonproliferative diabetic retinopathy (NPDR) in both eyes were randomly assigned to PRP with either a xenon arc or argon laser vs observation. The groundbreaking results, known by all ophthalmologists, showed a 50% reduction in severe vision loss after PRP. For the ensuing 4 decades, PRP was the gold standard for these patients.

Recently, the NEI-funded Diabetic Retinopathy Clinical Research (DRCR) Network reported the results of Protocol S, in which a similar group of 304 patients were randomized to PRP or treatment with anti-VEGF injections. After 2 years, ranibizumab was found to be noninferior to PRP in terms of visual acuity (primary outcome) and had superior outcomes in visual field loss, diabetic macular edema (DME), and vitrectomy rates. In patients with center-involved DME and PDR at baseline, the visual results with ranibizumab were superior. Interestingly, both groups had persistent neovascularization in 40% to 45% of patients after 2 years.

A combination of the RISE/RIDE and DRCR Network data led to FDA approval of ranibizumab for the treatment of DR in the presence or absence of DME; aflibercept is approved for a similar indication based on similar findings in the PANORAMA study. Thus, anti-VEGF injections alone can be used to treat PDR or severe NPDR. But is this the best management for these patients? The idea of what is the best management is discussed in detail in this issue.

The DRS and the ensuing Early Treatment Diabetic Retinopathy Study (ETDRS) established a numerical scale called the Diabetic Retinopathy Severity Scale (DRSS) where a 2-step change in the scale is considered significant. The scale is based on grading 7 standard color photographs for hemorrhages, microaneurysms, vascular abnormalities, and neovascularization. A change in the number and location of hemorrhages can dramatically change the scoring in either direction.

Given the mechanism of action of anti-VEGF agents, which reduce retinal hemorrhages and leakage, it is no wonder that they alter the DRSS so dramatically. However, this may not represent a similar change in the actual risk of progression to PDR in the future — the whole aim of the scale in the first place. Because injections have a limited durability, once they are stopped, the progression of DR resumes, often very dramatically. In contrast, once an eye responds to PRP, stability of the DR change continues for many years. This raises the question again: What is the best long-term treatment of PDR? Over 2 years and with good insurance, anti-VEGF agents surely win. But over the long term, I am not so sure that anti-VEGF agents have a clear advantage. RP

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