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Treatment for Severe Nonproliferative Diabetic Retinopathy
Role of anti-VEGF therapy remains controversial. Cheryl Guttman Krader reports
Is anti-VEGF therapy the best option for managing severe nonproliferative diabetic retinopathy (NPDR) without diabetic macular oedema (DME)? Two noted retina specialists debated the pros and cons of the question at a recent conference of the AAO.
Speaking in favour of routinely treating severe NPDR with anti-VEGF injections, Diana V Do MD provided an update on the scientific evidence supporting intervention. Ramin Tadayoni MD, PhD, offered several reasons defending the position that the best treatment for severe NPDR without DME is regular observation.
ARGUING FOR ACTION Dr Do began by offering an analogy between DR and coronary artery disease.
“Diabetic retinopathy is a chronic condition that is very similar to coronary artery disease as both conditions progress over time. Our colleagues in medicine routinely prescribe and proactively treat patients who have coronary artery disease with statins to lower the risk of complications,” she said.
“We know if left untreated, DR most likely will progress and lead to vision loss. If we have effective therapy, why are we not offering it to our patients?”
Underscoring the risk of not intervening, Dr Do cited data showing 50% of eyes with severe NPDR followed with observation will progress to proliferative disease within one year.
“Wouldn’t it be more beneficial to stop this progression? There is incontrovertible evidence demonstrating the benefit of anti-VEGF therapy for reversing DR severity,” she said.
The evidence included findings from the RISE and RIDE studies investigating ranibizumab for DME as well as subsequent PANORAMA study results showing aflibercept injected every 16 weeks significantly reversed retinopathy.
Data from studies investigating anti-VEGF injections for DR also show the treatment reduces the risk of vision-threatening complications or DME formation.
“In fact, the number needed to treat to prevent one of these complications is only three,” Dr Do said.
In addition, anti-VEGF therapy provides a vision benefit compared with observation. An analysis of mean area under the curve for change in BCVA from baseline to week 100 in the PANORAMA study showed a significant difference favouring the aflibercept group versus sham-treated controls.
“Severe NPDR should be routinely treated with anti-VEGF therapy because it targets the pathophysiology and has so many obvious benefits. Let’s be proactive and offer this effective and safe treatment to our patients rather than watching them get worse,” Dr Do concluded.
THE EVIDENCE FOR ESTABLISHED TREATMENT In 1968, participants in the Airlie House Symposium created the base for performing fundus examinations of diabetic patients. Subsequently, the Early Treatment Diabetic Retinopathy Study Research Group clarified methods for observing patients with DR and criteria for intervening with laser photocoagulation.
Tasked with proving that the long-established recommendations are as good as or better than the newer approach using anti-VEGF injections, Dr Tadayoni said the most important information comes from DRCR.net Protocol W—a two-year randomised trial that found no visual acuity benefit comparing eyes receiving preventive anti-VEGF therapy to controls managed with observation plus antiVEGF therapy if complications developed.
“Observation with photographic documentation every three months is less burdensome and is less invasive than anti-VEGF therapy. It is not surprising, therefore, that patients who begin antiVEGF treatment, even for PDR, are often lost to follow-up,” he said.
In another randomised trial of PDR treatment, approximately half of the patients in the anti-VEGF arm were lost to follow-up over five years. This is much worse than with regular observation, he noted.
Cost of care also weighs in favour of regular observation. Highlighting the cost of anti-VEGF therapy, Dr Tadayoni cited data from one cost-effectiveness analysis that found the cost of anti-VEGF treatment versus panretinal photocoagulation exceeded $700,000 per quality-adjusted life-year.
He also pointed out a lack of strong evidence to show anti-VEGF treatment improves DR beyond its impact on indirect signs. Two studies performed by Dr Tadayoni and colleagues showed vessel reperfusion was not found on imaging using ultra-widefield fluorescein angiography and widefield OCT angiography, respectively, despite improvement in the DRSS on colour fundus photography.
Dr Tadayoni said anti-VEGF therapy for NPDR may protect against PDR as long as the treatment continues. Once it stops, the consequences may still include the development of neovascular glaucoma and significant loss of vision.
“Observation is non-inferior to anti-VEGF injections in terms of effect on visual acuity and non-perfusion, and it is superior to antiVEGF therapy because it is less invasive and available worldwide. Regular observation leading to timely treatment has already prevented blindness in millions of patients, and as the less expensive option, it could save money that could be used to prevent blindness in other patients. Clearly the best treatment for severe NPDR without DME is regular observation,” he concluded.
The debate took place during the 2021 Retina Subspecialty Day at the AAO conference in New Orleans, Louisiana, USA.
Diana V Do MD is a Professor of Ophthalmology and Vice Chair of Clinical Affairs, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, California, USA. dianado@stanford.edu
Ramin Tadayoni MD, PhD, is a Professor of Ophthalmology at Paris University and chairman at Lariboisière, St Louis, and Rothschild Foundation hospitals, Paris, France. ramin.tadayoni@lrb.aphp.fr
