Proliferative diabetic retinopathy (PDR) is a leading cause of vision loss in patients with diabetic retinopathy (DR) and is characterised by the growth of new abnormal vessels on the retina or optic disc that can result in sight-threatening complications such as vitreous haemorrhage and tractional retinal detachment (TRD).1 Without treatment, nearly 50% of patients with high-risk PDR experience severe vision loss within five years.2 The pro-angiogenic cytokine vascular endothelial growth factor (VEGF) is considered the major factor responsible for neovascularization in PDR.3
Panretinal photocoagulation (PRP) has been the standard of care for PDR for over 40 years,2 and has shown great success in inducing regression of neovascularization and disease stabilization.4 However, it is associated with side effects including choroidal effusions, exudative retinal detachments, macular oedema, loss of peripheral visual field, and decreased night vision.5 Furthermore, around 5% of eyes with PDR lose vision despite PRP treatment.2 Therefore, there is a need for alternative therapeutic approaches.
The emergence of intravitreal agents that inhibit VEGF-A, such as ranibizumab (Lucentis; Genentech), aflibercept (Eyelea, Regeneron), bevacizumab (Avastin, Genentech), and pegaptanib (Macugen, Eyetech Inc.) has transformed the management of diabetic macular edema (DME), retinal vein occlusion and age-related macular degeneration (AMD). In the RIDE/RISE phase III clinical trials, which evaluated the efficacy and safety of ranibizumab for DME, monthly intravitreal injections of ranibizumab delayed progression to PDR.6 It is, therefore, not surprising that interest has risen in anti-VEGF agents in the prevention and treatment of PDR.
The Diabetic Retinopathy Clinical Research Network (DRCR.net) protocol S (Prompt PRP versus Intravitreous Ranibizumab with Deferred PRP for PDR) was the first large, prospective trial to compare PRP to anti-VEGF treatment in the treatment of PDR. The study found that treatment with ranibizumab resulted in visual acuity that was noninferior to PRP treatment at 2 years (mean best corrected visual acuity letter [BCVA] improvement at 2 years was +2.8 in the ranibizumab group versus +0.2 in the PRP p < 0 .001 for noninferiority). Ranibizumab treatment was also significantly (p < 0.001) superior to PRP in terms of peripheral visual field loss, vitrectomy, and DME development. One eye in the ranibizumab group developed endophthalmitis.7
In a phase IIb, single-blind, non-inferiority trial (CLARITY), 232 patients with type 1 or 2 diabetes and PDR were randomized to receive intravitreal aflibercept or standard care with PRP. Over the year, aflibercept patients received a mean of 4.4 injections, including the 3 loading doses specified in the protocol. The aflibercept group had a superior improvement in BCVA at 1 year compared with those treated with PRP (mean BCVA difference +3·9 lettffers, p<0.0001). At 1 year, 89% of patients in the aflibercept group had no DME, compared with 71% in the PRP arm. The incidence of vitreous haemorrhage was 18% in the PRP group, compared to 9% in the aflibercept group. No eyes in the study developed endophthalmitis, retinal detachment, iris neovascularization, or neovascular glaucoma.8 The study’s chief investigator, Sobha Sivaprasad, said: “This study is the first to show superior visual outcomes with an anti-VEGF agent, when compared to PRP, in proliferative diabetic retinopathy without baseline macular oedema. These are significant findings for an eye condition that has been treated with PRP as standard-of-care for the past 40 years to demonstrate that aflibercept could potentially be adopted as an alternative treatment option, in the first year, in compliant PDR patients in the future.”
Anti-VEGF agents have also shown a disease-modifying effect in terms of improvement in both DME and diabetic retinopathy severity score (DRSS), a clinically useful outcome measure that determines both anatomic and functional improvement.9 The phase III PANORAMA study investigating aflibercept treatment for moderately severe to severe PDR (NCT02718326) and the phase III DRCR.net Protocol W trial (NCT02634333) investigating anti-VEGF agents for the prevention of PDR, are currently ongoing.
Anti-VEGF agents may also be useful for patients with PDR who develop vitreous haemorrhage. A recent case series showed that intravitreal injections of bevacizumab alone could manage vitreous haemorrhage in almost one-third of patients.10 However, a phase III clinical study found little difference between ranibizumab and saline injections on the rate of vitrectomy at 16 weeks in 261 eyes with vitreous haemorrhage from PDR.11 There was a short-term benefit of ranibizumab on visual acuity, fewer recurrent vitreous haemorrhages, and increased chance of completing PRP, but there more studies are needed before the role of anti-VEGF agents is established in this indication.
Although the findings of CLARITY have caused excitement in the ophthalmology community, we need to consider several factors before switching to anti-VEGF agents as first-line treatment for PDR. While PRP is usually completed in two to four visits, intravitreal anti-VEGF agents require continued treatments, which imposes a substantial burden on patients and their caregivers. In the CLARITY clinical trial, 9% of participants did not complete the one-year visit, and in the DRCR.net protocols, 12% of participants did not complete the two-year visit. However, recent data suggest that an individually planned regimen may be as effective as monthly ranibizumab for AMD, easing the burden of treatment.12 Another important issue is cost; anti-VEGF treatments are expensive.13 Safety is a further consideration: bevacizumab has been reported to cause TRD in patients with severe PDR.14 In addition, controversy persists regarding the systemic safety of anti-VEGF treatments, especially in diabetic patients with significant vascular comorbidities. A 2015 meta-analysis revealing a possible increased risk of death in patients who received 2 years of monthly treatment.15
In terms of prevention, we need to know when to intervene and in whom. In a recent presentation at Retina 2018, Michael Ip suggested that intervention should be based on risk; an analysis of RISE/RIDE data suggests that patients with moderately severe or severe DR at baseline showed the greatest improvements with ranibizumab treatment.16 Finally, there is a need for long-term data on the efficacy and safety of anti-VEGF agents. The five-year follow-up data from DRCR Protocol S are expected later this year and should provide valuable information on long-term safety and how many injections are needed to maintain the beneficial effects.
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