Choosing the right treatment for proliferative diabetic retinopathy

November 28, 2016

Retina specialists who are Diabetic Retinopathy Clinical Research Network investigators offer views on whether laser panretinal photocoagulation or anti-VEGF therapy deserves consideration as first-line treatment for proliferative diabetic retinopathy.

Reviewed by David J. Browning, MD, PhD and Judy E. Kim, MD

Take-home: Retina specialists who are Diabetic Retinopathy Clinical Research Network investigators offer views on whether laser panretinal photocoagulation or anti-VEGF therapy deserves consideration as first-line treatment for proliferative diabetic retinopathy.  

With the introduction of anti-VEGF therapy, clinicians have argued whether pharmacotherapy or laser panretinal photocoagulation (PRP) deserves consideration as the first-line treatment for proliferative diabetic retinopathy (PDR).

Since the results of the Diabetic Retinopathy Study were reported in 1981, PRP has been the gold standard treatment for PDR. Then, in 2015, anti-VEGF therapy with intravitreal ranibizumab (Lucentis, Genentech) emerged as a new option, based on findings from Diabetic Retinopathy Clinical Research Network (DRCR.net) Protocol S.

In that prospective, randomized study, the primary outcome analysis of mean change in visual acuity (VA) from baseline showed ranibizumab 0.5 mg was non-inferior to PRP at 2 years. Statistically, significant differences favoring ranibizumab were found in analyses of VA area under the curve over the course of the study, visual field sensitivity loss, vitrectomy rate, and incidence of diabetic macular edema (DME).

Debating the roles of PRP and anti-VEGF therapy for PDR, Judy E. Kim, MD, professor of ophthalmology, Medical College of Wisconsin, Milwaukee, named the level 1 evidence from Protocol S as one of five reasons why retina specialists should consider choosing pharmacotherapy.

Courtesy of Judy E. Kim, MDSpeaking as the proponent for PRP, David J. Browning, MD, PhD, a retina specialist in private practice, Charlotte Eye, Ear, Nose, and Throat Associates, Charlotte, NC, acknowledged that according to Protocol S, intravitreal ranibizumab is the winner as far as efficacy and safety are concerned.

He pointed out that it is an excellent choice for a patient whose medical insurance covers the cost. Looking at the issue with a global view and from an economic perspective, however, PRP is the obvious choice for managing the world’s PDR case burden.

Current statistics

 

“In a world where there are enough retina specialists, where people return reliably for care, and where there is adequate health insurance coverage, outcomes with intravitreal anti-VEGF therapy seem better, at least through 2 years,” Dr. Browning explained.

“However, we don’t live in that world. There are 17 million people in the world with PDR, many do not return reliably for care, and 70% of them live in countries with low or middle per capita gross national income, where the per capita total health care expenditure falls far below the cost of anti-VEGF treatment.”

As examples, Dr. Browning noted that the annual per capita health care expenditures in China and India, which represent the two largest countries in the world, are $420 and $75, respectively. In contrast, the average cost of intravitreal ranibizumab for 2 years is about $23,000, based on calculations performed with data from Protocol S.

Considering the findings of a recent cost evaluation of treatments for PDR, anti-VEGF therapy still is not economically feasible if the less expensive agent, bevacizumab (Avastin, Genentech), is used instead of ranibizumab, he added.

Discussing the cost-effectiveness of anti-VEGF therapy for PDR in wealthier countries that have a higher gross domestic product (GDP), Dr. Browning reviewed willingness to pay values that are used to assess the acceptability of a treatment with greater effectiveness than the standard but a higher cost. He explained that willingness to pay is expressed in terms of the incremental cost effectiveness ratio (ICER) in units of incremental cost per quality adjusted life year (QALY).

In the United Kingdom, the National Institute for Health and Care Excellence has stipulated $39,000/QALY as the ceiling for ICER. No explicit ceiling exists in the United States, but numbers mentioned range between $50,000/QALY and $150,000/QALY. And, as a rule of thumb, willingness to pay in any given country is equal to the median per capita GDP/QALY, Dr. Browning said.

“The ICER for intravitreal ranibizumab for PDR is more than $200,000/QALY,” Dr. Browning said. “On that basis, it is not even cost-effective in Luxembourg, which is the wealthiest country of the world with a per capita GDP of $104,359.”

 

Anti-VEGF treatment of choice

Speaking about why anti-VEGF therapy should be favored over PRP for PDR, Dr. Kim cited both its benefits compared with PRP and the limitations of PRP. She noted that the reduced need for vitrectomy with ranibizumab compared with PRP translates into reduced cost of care. In addition, Dr. Kim used data from Protocol S to refute the idea that PRP may at least be ideal for noncompliant patients.

“PRP is not a ‘once-and-done’ procedure, where we can say all is fine with a single treatment so it is fine for a noncompliant patient,” Dr. Kim said.

“In Protocol S, almost 50% of patients randomized to PRP required supplemental PRP to manage active disease at an average of 7 months after the initial session,” she explained. “We also know that PRP can cause or exacerbate DME. Therefore, PRP-treated patients still need to be monitored.”

Courtesy of Judy E. Kim, MDAnother argument against PRP is that laser treatment is not easily done in all patients. Patient pain thresholds vary widely, and while retrobulbar anesthesia makes the procedure tolerable, it also introduces its own set of complications. In addition, PRP is not possible in eyes with conditions that obscure visualization of the fundus, such as dense asteroid hyalosis, vitreous hemorrhage, small pupil, or dense cataract.

Dr. Kim said that inarguably, anti-VEGF therapy represents first-line treatment for PRP in an eye with DME. Anti-VEGF currently is the first-line therapy for eyes with center-involved DME. Furthermore, anti-VEGF therapy can improve macular non-perfusion, whereas PRP can worsen DME and cause vision loss.

“Anti-VEGF can treat both diseases,” Dr. Kim said. “In shoppers’ terms, anti-VEGF therapy in an eye with PDR and DME is a ‘buy-one, get-one-free’ situation. It is the ultimate in cost savings.”

Finally, Dr. Kim proposed that retina specialists apply a litmus test to determine which of the two options is superior.

“If it was your eye that had PDR, would you not want to be treated with anti-VEGF therapy and have the possibility of having an improved Diabetic Retinopathy Severity Score, less visual field loss, and less retinal destruction?” she asked. “We should congratulate ourselves that for the first time in 40 years, we have another option for our patients with PDR.”

 

 

David J. Browning, MD, PhD

E: djbrowning@carolina.rr.com

 

Judy E. Kim, MD

E:  jekim@mcw.edu

 

This article is based on presentations given at the 2016 Retina Subspecialty Day during the American Academy of Ophthalmology meeting.

Dr. Browning receives grant support from the DRCR.net, Regeneron Pharmaceuticals, Genentech, Novartis, Allergan, Alcon Laboratories, Pfizer, Aerpio Therapeutics, and Ohr Pharmaceuticals and is a consultant to Alimera Sciences.

Dr. Kim is vice chairperson of the DRCR.net, receives research support from Optos, and is on the advisory board of Genentech and Novartis.