More than a decade ago, a young patient with type 1 diabetes was referred to me for a second opinion.  Despite repeated interventions with panretinal photocoagulation (PRP) and vitrectomy, he had lost nearly all the vision in his right eye due to traction retinal detachment from proliferative diabetic retinopathy (PDR).  He was just starting to experience vision loss in his left eye from diabetic macular edema.  Although he had undergone full PRP in the left eye, his retinal neovascularization was persistent and highly active.  As we talked about treatment options, it was clear that he was terrified that he would go completely blind.

Fortunately, he presented at the threshold of the current anti-VEGF era.  He was one of the first patients that I treated with intravitreous anti-VEGF therapy.  His diabetic macular edema and PDR both improved dramatically.  The angry-looking fronds of retinal neovascularization practically disappeared.  Although he traveled a least a couple of hours to make each clinic appointment, he rarely if ever missed or rescheduled a visit.  A series of anti-VEGF treatments resulted in successful regression of his diabetic eye complications and 20/20 visual acuity that he maintains to this day.

At the time, this patient’s rapid PDR improvement seemed nearly miraculous.  Cases like his inspired many of us to start using intravitreous anti-VEGF more frequently for patients with recalcitrant ocular neovascularization and, in some cases, as first-line therapy for advanced diabetic eye disease.  Nonetheless, laser photocoagulation, which had proven to be an effective primary treatment for PDR over the past several decades, required far fewer treatments and was clearly successful in achieving extended regression of retinal neovascularization.  So what has the ensuing decade taught us about the relative advantages and disadvantages of anti-VEGF vs PRP for PDR?

Randomized controlled trial evidence supports the use of either of these treatment modalities for diabetic eye disease.  In 2015, the DRCR Network published the first randomized trial of intravitreous ranibizumab therapy vs PRP for PDR.  At the primary outcome point of 2 years, eyes treated with ranibizumab had mean visual acuity outcomes that were noninferior to those achieved with PRP.  Ranibizumab treatment resulted in more favorable outcomes than PRP with regard to superior average visual acuity over the course of 2 years, less peripheral visual field loss, lower rates of vision-impairing diabetic macular edema, and fewer vitrectomies.  The CLARITY study group subsequently reported results of a randomized trial of aflibercept vs PRP for proliferative disease and found superior visual acuity outcomes at 1 year in the aflibercept-treated eyes.

Long-term, 5-year results from Protocol S were published in JAMA Ophthalmology and presented for the first time at the American Society of Retina Specialists meeting in July.  These findings are critical to help understand the chronic course of eyes treated in the modern era for PDR.  Disappointingly, study retention was poor, with only 66% of participants completing the 5-year visit.  Thus, perhaps the first lesson to glean from this study is that patients with advanced diabetic eye disease may be at high risk for noncompliance with recommendations for follow-up and treatment.  Eyes treated with anti-VEGF in this study did need fewer injections after the first year, receiving on average approximately 7 injections in year 1 and 3 injections per year throughout years 2 through 5.  Fortunately, for the patients who successfully completed 5 years of follow-up, visual acuity results were excellent, with Snellen equivalent average vision of 20/25 in both treatment groups.  Similarly to 2 years, mean visual acuity results at 5 years with ranibizumab were noninferior to those with PRP.  Ranibizumab-treated eyes had lower rates of development of vision-impairing diabetic macular edema and retinal detachment.  Interestingly, although loss of peripheral visual field was less in the ranibizumab as compared to the PRP group, both groups demonstrated worsening visual field loss over time.

For the foreseeable future, these data are likely to be the longest term follow-up that we will have of eyes treated and prospectively followed according to a standardized regimen of anti-VEGF vs PRP for PDR.  The Protocol S findings suggest that anti-VEGF therapy is an effective and safe alternative to PRP in patients who are compliant with long term follow-up.  But is anti-VEGF the best choice for everyone with PDR?  No—absolutely not.  PRP is noninvasive and generally requires fewer treatment sessions.  It can be used safely in patients who are not candidates for anti-VEGF, such as pregnant women.  Most importantly, the duration of effect with PRP is much longer lasting, making issues with patient compliance of somewhat less concern.  Like many of my colleagues, I have treated several patients who responded well initially to anti-VEGF injections, but who were then lost to follow-up and reappeared after several months or years with florid neovascularization and irreversibly poor vision outcomes.

My opinion is that there is no clear winner in the contest for best treatment for PDR.   The decision to use anti-VEGF or PRP or even a combination of both, depends on both ocular and patient characteristics, such as presence of concurrent diabetic macular edema, patient compliance, and medical stability.  I am just grateful that we have 2 effective therapeutic alternatives that can be used to preserve and improve vision for patients with PDR.


Disclosure:  Dr Sun is a Chair of the DRCR Network and works on its diabetes initiatives, but this blog represents her personal opinion and is not written on behalf of the Network.

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