Research in context
Evidence before this study
Panretinal laser photocoagulation (PRP) is the standard of care for patients with proliferative diabetic retinopathy. Presently, three anti-vascular endothelial growth factor (anti-VEGF) therapeutic agents are administered by intravitreal injections to treat ophthalmic conditions. Bevacizumab and ranibizumab are monoclonal antibodies against VEGF-A. Before this trial, we reviewed PubMed articles published between Jan 1, 2005, and Jan 31, 2014, and there were eight short-term (3–6 months), randomised controlled trials comparing either bevacizumab or ranibizumab monotherapy or in combination with PRP versus PRP alone in high-risk patients with proliferative diabetic retinopathy. These randomised controlled trials showed new vessel regression with these biological agents within 3–4 months. Aflibercept is the latest anti-VEGF agent and it blocks all isomers of VEGF-A, VEGF-B, placental growth factor 1, placental growth factor 2, and galectin-1. To date, there have been no randomised controlled trials of aflibercept in patients with proliferative diabetic retinopathy.
We updated the literature review on March 1, 2017. A well designed multicentre clinical trial comparing ranibizumab monotherapy versus PRP in patients with high-risk proliferative diabetic retinopathy, with and without macular oedema, has been published. The primary outcome of this randomised controlled trial at 2 years showed non-inferiority of ranibizumab versus PRP in patients at a high risk of proliferative diabetic retinopathy with a median of ten injections over 2 years (seven injections in the first year). However, this trial has not changed clinical practice worldwide due to the perceived practical difficulties of delivering repeated intravitreal injections in patients with proliferative diabetic retinopathy. Additionally, the study only showed non-inferiority of best corrected visual acuity to PRP, albeit with beneficial secondary outcomes. Therefore, PRP remains the preferred choice. Additionally, a substantial proportion of patients after initial PRP are under long-term follow-up in retinal clinics to identify and treat reactivation of existing neovascularisation with supplemental PRP and these patients have been excluded from previous clinical trials. Therefore, the role of anti-VEGF in this patient cohort remains unclear.
Added value of this study
The CLARITY study is the first randomised controlled trial, to our knowledge, of intravitreal aflibercept in proliferative diabetic retinopathy and the results provide substantial evidence that the visual outcome of active proliferative diabetic retinopathy at 1 year with aflibercept therapy is superior to PRP. This study is also the first to show a superior visual acuity outcome with an anti-VEGF agent in eyes with proliferative diabetic retinpathy with no baseline macular oedema compared with PRP therapy. Furthermore, this effect was achieved with four aflibercept injections (a median of one injection after the three loading doses in a year) irrespective of the proliferative diabetic retinopathy risk status and previous PRP treatment history, providing important evidence that aflibercept therapy can be adopted as an alternative to PRP in the first year of therapy. The study also showed a significantly lower incidence of macular oedema and vitreous haemorrhage and fewer adverse effects on binocular visual acuity and visual fields with aflibercept compared with PRP, further highlighting the advantages of aflibercept over PRP with similar systemic adverse effects. Most importantly, the patient satisfaction scores suggest a patient preference for aflibercept therapy over PRP in a clinical trial setting.
Implications of all the available evidence
In the first year of therapy, aflibercept is an effective treatment for active proliferative diabetic retinopathy and might be adopted as an alternative option to PRP.