CONTROVERSIES IN CARE

PRP vs Anti-VEGF for PDR: Is It Time for Laser Ablation?

EDITED BY MICHAEL COLUCCIELLO, MD

Panretinal photocoagulation (PRP) has been the “gold standard” for several decades to prevent severe vision loss associated with vitreous hemorrhage and/or traction macular detachment associated with “high-risk” proliferative diabetic retinopathy, following evidence of efficacy from the Diabetic Retinopathy Study.¹

In 2015, the Diabetic Retinopathy Clinical Research Network released two-year results from the Protocol S study.² This study showed that monthly intravitreal injections of 0.5 mg of ranibizumab (for a minimum of three consecutive months) were associated with one-third less incident macular edema and better visual acuity and visual field outcomes than in those managed with PRP while protecting against vitreous hemorrhage and traction retinal detachment.

Fewer subsequent vitrectomies were necessary in patients with PDR managed with intravitreal ranibizumab, compared to those managed with PRP laser. Previously, intravitreal ranibizumab (Lucentis, Genentech, South San Francisco, CA) was shown to reduce the risk of DR progression; in fact, ranibizumab-treated eyes could experience improvement in DR severity.³

However, the need for monthly anti-VEGF injections (at least for a period of time) and postinjection serial monitoring for recurrent neovascularization (requiring retreatment) may be challenging for the patient from a compliance standpoint, while panretinal laser may successfully be done in one sitting.

Therefore, as clinicians, we are left with a decision: How do we best handle the patient with active PDR in 2016? We are fortunate to have the perspective of Rishi Singh, MD, of the Cole Eye Institute, and Andrew Moshfeghi, MD, of USC Eye Institute, to aid in our decision process.

REFERENCES

Cautious Optimism Is Warranted

ANDREW MOSHFEGHI, MD

The results of the DRCRnet Protocol S study¹ are not only groundbreaking, but they also provide scientific validation of our contemporary understanding of the pathophysiology of untreated proliferative diabetic retinopathy.^2-3

By blocking VEGF with ranibizumab, we witnessed significant anatomic and functional improvements in this disease: regression or improvement in retinopathy severity, as well as statistically significant improvements in visual acuity and preservation of visual field, compared with the laser cohort.

Proliferative diabetic retinopathy. Top row: Color, red-free, and fluorescein angiogram, right eye, showing microaneurysms, blot hemorrhages, exudates, and retinal capillary nonperfusion associated with retinal neovascularization inferior-nasal to the optic nerve. Bottom row: Left eye of the same individual showing similar findings, along with retinal neovascularization also superior-nasal to the optic nerve.

As previously mentioned by Dr. Colucciello, additional anatomic benefits of managing PDR with anti-VEGF monotherapy and rescue scatter laser (hereafter referred to as “anti-VEGF monotherapy”) include a lower likelihood of developing vitreous hemorrhage and — along the same lines — a reduced likelihood of requiring vitrectomy surgery, compared with the laser cohort.

Another practical benefit of anti-VEGF monotherapy for PDR, besides mitigating retinopathy severity, is that we can also thwart the development of DME and treat it simultaneously if it has already presented.

WHAT WE DIDN’T LEARN

What Protocol S did not reveal, however, is whether the sustained therapeutic benefit of anti-VEGF monotherapy is as durable for PDR as Protocol I demonstrated that it was for DME more than five years and with very few injections in the later years.

I suspect that it might not have the lasting benefits in controlling DR severity after the first two years as it had for controlling DME. In other words, DME was controlled in the long term with very few injections on average in years 3, 4, and 5 in Protocol I, but I am skeptical that PDR will be similarly well controlled in later years (years 3 through 5) in Protocol S when perhaps only a few injections are given each subsequent year, with no peripheral scatter laser.

If this turns out to be the case, then the utility of the anti-VEGF monotherapy treatment paradigm for PDR may be prudently restricted only in those patients who also require anti-VEGF agents for the management of comorbid DME.

While it might also be tempting to treat patients with both DME and PDR with only anti-VEGF agents and no scatter laser in perpetuity, this may only be indicated in patients in whom adherence to the treatment regimen and who keep appointments reliably over time can be anticipated.

Patients change insurance plans, move to other locations, forget to keep follow-up appointments, and — as a result – they are lost to follow-up. If they never received peripheral scatter laser, then there would be a real concern for the undesirable complications of untreated or undertreated PDR and the risk of irreversible loss of vision.

WHAT ABOUT “GOOD” PATIENTS?

One may ask, “But can’t we use anti-VEGF monotherapy and no scatter laser for our PDR patients (and no DME) with a demonstrated history of strong adherence to a treatment regimen and a documented record of keeping appointments reliably?”

In the absence of good data to help answer this question, this decision will be up to each individual physician and each patient to decide, but for now, the risks of foregoing scatter laser appear to be outweighed by the benefits of doing so. We will have to wait until we have the ability to review additional long-term data from Protocol S before we can reevaluate this conservative approach for the vast majority of our PDR patients.

Finally, one must bear in mind that the data from Protocol S refer to anti-VEGF monotherapy with ranibizumab and not all anti-VEGF agents in general. Although it may turn out to be case that similar results would be observed with aflibercept or bevacizumab, additional studies may be necessary to answer that question unequivocally.

REFERENCES

Anti-VEGF vs Laser for PDR

RISHI SINGH, MD

The investigators for the DRCRnet Protocol S should be congratulated for their effort in evaluating whether prompt PRP vs intravitreal ranibizumab treatment (IRT) resulted in similar outcomes.

The study results clearly show that IRT treatment is noninferior to PRP treatment for proliferative diabetic retinopathy regarding both vision over the two-year period and complications from PDR, including the most devastating, such as neovascular glaucoma and the need for vitrectomy.

PROCEED WITH CAUTION

However, before instituting IRT therapy in patients for PDR, it’s important to consider the larger issues that IRT treatment doesn’t address. For example, despite aggressive anti-VEGF treatment in some of more recent randomized, clinical trials, patients still progress to proliferative disease.

An analysis from the RISE/RIDE study demonstrated that, despite 24 IRT treatments, 10% of patients went on to develop PDR.¹ In Protocol I, which represented more of a real-world approach, almost 20% went on to develop PDR despite a significant number of IRT injections.²

Another factor to consider is that, prior to Protocol S, IRT treatment did not result in a regression of diabetic retinopathy in a majority of patients. Data from RISE/RIDE showed that only 13% of patients experienced a three-step reduction in retinopathy score, while 37.6% experienced a two-step reduction.³

Panretinal laser also has significant long-term efficacy, which has been documented extensively in the literature.⁴ Data from the ETDRS on the surviving members showed that 42% had vision of 20/20 or better, and 84% had 20/40 or better with a median follow-up of 16.7 years.

Anti-VEGF also is quite expensive compared to PRP laser. An extrapolation of the data from Protocol S yielded a total one-year treatment cost of $20,000 for IRT patients and $3,750 for PRP-treated patients.

THE ROLE OF FOLLOW-UP

Finally, the true outcome of any of these treatments can be assisted with good follow-up. Unfortunately, the DME population has very poor follow-up, compared to other patients receiving anti-VEGF for various conditions.

We conducted a retrospective review at our practice and found that patients with DME had an appointment no-show rate of 29.9%, compared to those with exudative AMD, who had a no-show rate of 10.4%.

This finding makes complete sense given the reference population of those with DME, typically aged 20-74 years old, who are currently employed and managing multiple appointments, along with their eye visits.

In summary, IRT is breakthrough therapy for patients with diabetic eye disease. However, we have only short-term efficacies from studies employing it for PDR, it requires multiple injections and compliant patient follow-up, some patients progress despite aggressive anti-VEGF treatment, and it’s expensive.

Panretinal laser should still be considered as first-line treatment in those with PDR. RP

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