Location is everything, especially in the eye.

Inner fluid volume measured by optical coherence tomography (OCT) differs significantly in its amount, shape and distribution compared with outer fluid volume. It also is associated with larger macular holes and poorer postoperative vision in contrast with outer fluid volume.

These findings suggest that inner fluid volume represents a retinal degenerative change associated with more advanced macular holes, according to Kotaro Tsuboi, MD, a visiting scholar from Aichi Medical University in Nagakute, Aichi, Japan, at Oregon Health & Science University.

The results are from a study in which investigators took a retrospective look at intraretinal cystoid spaces, which are often present next to macular holes, using the AngioVue OCT angiography (OCTA) and Avanti RTVue XR (Optovue). All study patients had undergone a successful surgery to close a macular hole that included pars plana vitrectomy with internal limiting membrane peeling.

Clinical results analyze dexamethasone implant effect on macular thickness

The OCTA software in the Avanti machine produced volumetric data and custom software,1 and generated volume-rendering OCT images of the intraretinal fluid spaces, Tsuboi explained.

The study included 42 eyes of 39 patients. Using the International Vitreomacular Traction Study classification, investigators classified the macular holes as small in 11 eyes (26%), medium in 11 eyes (26%) and large in 20 eyes (48%). Sixteen eyes (38%) had vitreomacular traction (VMT). Of the 42 eyes, 39 (93%) underwent combined phacovitrectomy and all eyes were pseudophakic postoperatively.

Human amniotic membrane in the surgery of recurrent macular holes

Importantly, large macular holes were associated with increased inner fluid volume compared with small macular holes, a difference that reached significance (

 = .0030). No differences in outer fluid volume were seen in association with the size of the macular holes, Tsuboi reported. In addition, VMT did not seem to drive the inner and outer fluid volumes, which were similar in eyes with and without VMT.

Inner fluid volume and minimal macular hole size had a significant effect on postoperative visual acuity (Pearson 

 = .0045, respectively), whereas basal macular hole size (

= .27) did not. The multivariate analysis found that inner fluid volume was the only significant factor affecting the postoperative 12-month visual acuity (

The main takeaways from the study were that OCT showed that inner fluid volume differed significantly in amount, shape and distribution compared with outer fluid volume; it was associated significantly with large macular holes and poorer postoperative vision in contrast with outer fluid volume.

Visualisation with en-face OCT offers value for ophthalmologists

Further, inner fluid volume may represent dysfunction of the Müller cells and a degenerative change associated with more advanced macular holes.

Guo Y, Hormel TT, Xiong H, Wang J, Hwang TS, Jia Y. Automated segmentation of retinal fluid volumes from structural and angiographic optical coherence tomography using deep learning. 

This article was adapted from Tsuboi’s presentation at the Association for Research in Vision and Ophthalmology 2021 virtual annual meeting. He has no financial interest in this subject matter.

Articles

Results may represent a retinal degenerative change.

Inner fluid volume and its role in macular hole repair

Detecting age-related macular degeneration (AMD) as early as possible is the best strategy for preventing irreversible damage down the line. Fluorescence lifetime imaging ophthalmoscopy (FLIO), a noninvasive imaging method, may help delay progression by initiation of carotenoid supplementation, according to Jace Buxton, a medical student at the University of Utah School of Medicine in Salt Lake City.

FLIO’s characteristic pattern is a ring-shaped area of prolonged mean autofluorescence lifetimes around the macula. Buxton and colleagues conducted a study in which they investigated the changes in the autofluorescence lifetimes over time in patients with AMD to better understand disease progression and the responses to treatment.

The study evaluated 28 patients with a mean age of 73 years using a protype FLIO instrument (Heidelberg Engineering). Patients were followed for a mean of 17 months (range, 6-35). FLIO was performed to investigate a 30° retinal field centred on the fovea, Buxton explained.

Fundus autofluorescence was excited at 473 nm, and FLIO lifetimes were recorded in short (498-560 nm) and long (560-720 nm) spectral channels (SSC and LSC, respectively) (Figure).

The investigators reported increases in the values obtained in both the SSC and LSC over time. At baseline, the FLIO lifetimes in the outer ring of a standardised early treatment diabetic retinopathy study grid were 297 ± 54 picoseconds (ps) and 405 ± 58 ps, respectively, in the SSC and LSC. At the follow-up evaluation, the respective values for the same areas were 306 ± 59 ps and 411 ± 57 ps, changes that reached significance in both spectral channels (P < .01). The central area did not exhibit any significant changes in either spectral channel. The average 12-month prolongation of FLIO lifetimes in the outer ring was 7 ± 20 ps and 7 ± 13 ps in the SSC and LSC.

Buxton pointed out that the rate of progression varied among patients and even between eyes of the same patient. The investigators concluded that FLIO may be useful to monitor AMD progression as well as the effectiveness of treatment approaches. For example, in 3 patients treated with anti-VEGF, there was a 10-ps annual decrease in the autofluorescence lifetimes.

This article was adapted from Buxton’s presentation at the Association for Research in Vision and Ophthalmology 2021 virtual annual meeting. He has no financial interests related to this subject matter.

Fluorescence lifetime imaging ophthalmoscopy may be useful to monitor the progression of AMD as well as the effectiveness of treatment approaches.

Using FLIO to monitor AMD progression

Noninfectious uveitis (NIU) comprises a group of diseases characterised by inflammation of the uvea and the surrounding tissue. NIU affects approximately 300,000 adults in the United States, with a majority being of working age.

 The goals of NIU treatment are to control inflammation, reduce tissue damage and potentially restore vision loss, while minimising adverse effects.

 Treatment of NIU is often challenging because of significant variability in the disease presentation and the presence of accompanying systemic disorders.

The current standard of care in NIU treatment includes corticosteroids, which can be delivered via local or systemic routes. Systemic therapy may be desirable in managing NIU with concomitant systemic disease and/or when both eyes are affected. However, systemic corticosteroid treatment is associated with the risk of steroid-related adverse effects. Systemic and local (intra/periocular) steroids also require frequent dosing.

Uveitis: A leading and underestimated cause of visual morbidity in patients

Sustained-release intraocular corticosteroid implants provide an efficacious, long-lasting and local treatment option for NIU. The implants have particular advantages for the relatively young patient population affected by NIU, who may be challenged to return for frequent follow-up or wish to avoid systemic treatment because of concerns about fertility. In this category, Retisert (fluocinolone acetonide 0.59 mg; Bausch + Lomb) and Yutiq (fluocinolone acetonide 0.18 mg; EyePoint) both provide the drug for up to 3 years. Retisert is implanted via a procedure, whereas the smaller Yutiq implant is delivered by an in-office intravitreal injection. Both implants help reduce the recurrence of uveitis, improve or stabilise vision, and limit the need for concomitant anti-inflammatory medications.

Although both implants are associated with risks of IOP elevation and cataract development, these risks are generally lower with the lower-dose Yutiq than Retisert

 and can be minimised by identifying steroid responders with a trial of sub-tenon/intraocular triamcinolone or intraocular dexamethasone.

Treatment with the sustained-release Yutiq implant can reduce recurrence of uveitis and the need for additional adjunctive anti-inflammatory therapies and provide substantial improvement to patients’ vision and quality of life. Although it stands to reason that using a single-dose, sustained-release corticosteroid implant such as Yutiq would provide an overall benefit, formal cost-effectiveness analysis helps test this assumption and guide beneficiary decisions.

The largest payers in the United Kingdom and United States are the National Health Service and the Department of Health & Human Services, respectively. In the US, the Medicare programme cost was $644 billion in 2019, corresponding to 15% of federal spending, and Medicare spending has increased, on average, by 4.8% per year since 2010.

AAO: Study confirms Phase III results for uveitis treatment

To manage the challenge of increased healthcare costs, governments could increase taxes or divert tax dollars towards healthcare and away from other vital parts of society, such as education and transportation. As no such policy is easy to implement, cost-effectiveness analyses can be applied to help optimise the use of healthcare resources.

In cost-effectiveness analyses, costs are determined using historical data and/or mathematical models and are then assessed in the context of health outcomes to determine whether one intervention could be more favourable than an alternative (eg the standard of care). Incremental cost-effectiveness ratios (ICERs) describe the difference in mean costs of 2 interventions divided by differences in the mean outcomes. 

In the context of NIU, a more desirable therapy may be one that offers cost savings while providing the same visual outcome and a longer duration. In addition to directly benefiting patients with NIU, a more cost-effective treatment allows scarce healthcare resources to be allocated elsewhere, thus indirectly benefiting all patients and society as a whole.

The UK’s National Institute for Health and Care Excellence (NICE) recently initiated a cost-effectiveness analysis that compared the fluocinolone acetonide (FA) intravitreal implant 0.18 mg (Yutiq in the US) against the dexamethasone intravitreal implant 0.7 mg (Ozurdex) for treatment of recurrent NIU.

The study used results from a 36-month parallel, randomised, double-blind trial that compared FA implant with sham injection

 and evaluated 3 scenario analyses, each assuming a different level of efficacy for the dexamethasone implant (HR, dexamethasone vs sham, 0.456 [derived from an earlier cost-effectiveness study]; HR, dexamethasone vs FA implant, 1 and 0.7). Additional assumptions also were incorporated into a de novo Markov model to carry out the cost-effectiveness assessment.

FDA accepts Bausch Health, Clearside Biomedical's resubmitted Xipere NDA

The study found that the FA implant extendedly dominated the dexamethasone implant in the first set of analyses, whereas dexamethasone dominated and extendedly dominated the FA implant in the second and third, respectively. Across all analyses, the ICER of the FA implant vs sham injection/standard of care ranged from £12,325 to £30,153 ($16,896 to $41,335) per quality-adjusted life-year (QALY). 

Additional analyses found that the FA implant was dominant (more effective, lower cost) in some scenarios, with most ICERs below £20,000 ($27,417) per QALY gained. Based on these additional analyses, the NICE Appraisal Committee recommended the FA implant as a cost-effective use of NHS resources for recurrent NIU affecting the posterior segment.

AAO: Fingolimod for MS offers disease control with no development of uveitis

The study had several limitations. First, it was unclear to the authors whether FA implants would be administered as a first, second or third treatment line in the treatment pathway, which would determine the most relevant comparator. Second, it was unclear whether subsequent FA implants should be considered, which would change the scope of the appraisal. 

In addition, the model structure may not have adequately represented the natural course of the disease and the effect of treatment on visual acuity, and only accounted for a single, treated eye, whereas NIU may often develop into a bilateral disease. Finally, no quality-of-life data were captured in the clinical study of the FA implant on which the model was based.

I have found the FA implant (Yutiq) to be an effective treatment for NIU, and I discuss the option with patients who have chronic and/or recurrent NIU affecting the posterior segment and have previously responded to shorter-duration intraocular steroid injections without associated IOP elevation. I prefer localised treatment over systemic therapy, especially in patients with unilateral disease and no extraocular inflammatory findings. In my experience, Yutiq offers long-term control of intraocular inflammation and macular oedema.

Pearls for ocular surgical success in patients with chronic uveitis

One major drawback of modelling-based cost-effectiveness analyses is the reliance on assumptions that may not be truly representative of routine clinical practice. In the real world, treatment must be individualised. Cultural/geographical variations in clinical practice patterns also can alter the course of treatment. Still, although some assumptions and limitations are inherent in cost-effectiveness analyses, this research provides evidence on which to base decisions about the value of care.

1. Thorne JE, Suhler E, Skup M, et al. Prevalence of noninfectious uveitis in the United States: a claims-based analysis. JAMA Ophthalmol. 2016;134(11):1237-1245. doi:10.1001/jamaophthalmol.2016.3229

2. Valenzuela RA, Flores I, Urrutia B. New pharmacological strategies for the treatment of non-infectious uveitis. a minireview. Front Pharmacol. 2020;11:655. doi:10.3389/fphar.2020.006553

3. Jaffe GJ, Pavesio, CE; Study Investigators. Effect of a fluocinolone acetonide insert on recurrence rates in noninfectious intermediate, posterior, or panuveitis: three-year results. Ophthalmology. 2020;127(10):1395-1404. doi:10.1016/j.ophtha.2020.04.0014

4. Callanan DG, Jaffe GJ, Martin DF, Pearson PA, Comstock TL. Treatment of posterior uveitis with a fluocinolone acetonide implant: three-year clinical trial results. Arch Ophthalmol. 2008;126(9):1191-1201. doi:10.1001/archopht.126.9.11915.

5. National Health Expenditure Data. Centers for Medicare & Medicaid Services. December 17, 2019. Accessed July 1, 2021. https://www.cms.gov/Research-Statistics-Data-and-Systems/Statistics-Trends-and-Reports/NationalHealthExpendData6

6. The federal budget in 2019: an infographic. Congressional Budget Office. April 15, 2020. Accessed 1 July 2021. https://www.cbo.gov/publication/563247

7. Pouwels XGLF, Petersohn S, Carrera VH, et al. Fluocinolone acetonide intravitreal implant for treating recurrent non-infectious uveitis: an evidence review group perspective of a NICE single technology appraisal. Pharmacoeconomics. 2020;38(5):431-441. doi:10.1007/s40273-019-00851-z

Lally practices at New England Retina Consultants and is an attending surgeon at Baystate Medical Center in Springfield, Massachusetts. He is an assistant professor in the Department of Surgery at the University of Massachusetts Medical School-Baystate and an assistant professor of ophthalmology at the University of Massachusetts Medical School.

Long-term treatment helps chronic, vision-threatening disease.

Sustained-release anti-inflammatory therapy proves valuable in NIU

Inherited retinal diseases (IRDs) comprise a diverse group of clinical phenotypes that result from mutations in a variety of genes. Although it has been known for some time that a given IRD can arise from alterations in 1 or more genes, there has been little impetus to pursue genetic testing to identify a patient’s specific mutation because information gleaned from these tests often did not change clinical practice. With the exception of retinal dystrophy due to mutations in the RPE65 gene, there are no approved effective therapies for IRDs.

It takes a village to beat visual system diseases in children

Eye care professionals have typically monitored patients with these diseases for progressive vision loss without being able to provide treatment beyond nutritional supplements, and these have not demonstrated significant benefit with respect to disease progression or long-term vision outcomes. In the absence of effective therapy, many patients lose hope that they can prevent further vision loss and forgo their annual eye health exams.

Fortunately, the landscape of IRD therapies is evolving. In 2017, the FDA approved voretigene neparvovec-rzyl (Luxturna; Spark Therapeutics), a gene therapy for the treatment of biallelic RPE65-mutation-associated retinal dystrophy. Voretigene neparvovec-rzyl utilises an engineered adeno-associated virus as a vector for delivering a functional copy of the RPE65 gene to retinal cells, thereby restoring retinal cell function. This approval validated the use of gene therapy in the treatment of IRDs, creating new hope for patients across a variety of degenerative diseases, including X-linked retinitis pigmentosa (XLRP), choroideremia, achromatopsia, Stargardt disease and other forms of retinitis pigmentosa due to mutations in the USH2A, RHO or CEP290 genes, the latter of which causes Leber congenital amaurosis.

Retinal gene therapy clinical trials are addressing disease at core

Although these conditions can have variable age of onset, with the exception of congenital achromatopsia, which is present from birth, many can present in the paediatric age group. With at least 24 IRD clinical trials ongoing in the United States, and additional studies of stem cell therapy in several IRD indications under way, hope is on the horizon for many patients with IRDs who were previously considered untreatable.

It is gratifying to have multiple IRD therapies moving towards approval, but realising the potential of these therapies requires that eye care professionals, especially those who see paediatric patients, reorient themselves within an evolving landscape. A key first step in developing a new perspective and approach to clinical practice is recognising the importance of genetic testing in empowering patients to understand the fundamental cause of their disease and identify opportunities for participating in clinical trials. Although access to IRD genetic testing has historically been limited because of lack of reimbursement for a test that had no impact on clinical practice, 2 programmes currently provide free testing that can be performed by the patient at home or by a physician or eye health professional during a regular clinic visit.

Corneal crosslinking outcomes appear to justify its use in paediatrics

The My Retina Tracker Program developed by the Foundation Fighting Blindness in partnership with Blueprint Genetics and InformedDNA and supported by several pharmaceutical companies, including AGTC, allows any provider caring for a patient with an IRD to offer that patient genetic testing. Physicians who enrol patients in the programme receive free testing kits in the mail and collect a genetic sample from the patient through a simple blood draw or saliva sample, the latter of which patients can perform themselves at home. For paediatric patients with IRDs, the ability to perform saliva testing in particular is both easy and efficient, removing any fear of the needles often associated with other lab tests.

The physician obtains informed consent from the patient or parent and completes a requisition form for the genetic test, and the forms and sample are returned to Blueprint Genetics in a prepaid envelope. The test currently evaluates 285 genes associated with IRD, and now also includes mitochondrial DNA testing. Genetic test results are typically returned in 3 to 4 weeks.

Inherited retinal disease: Treatment overview (video)

The programme also offers free genetic counselling to patients through InformedDNA, which provides telephone-based genetic counsellors who contact the patient to review and discuss the test results. The ID Your IRD program, which is offered through the genetic testing company Invitae and sponsored by Spark Therapeutics, offers a similar programme that tests 293 IRD-associated genes, but does not include the 

Given the progressive nature of many IRDs, gene therapy may provide optimal benefit when administered early in the course of disease when fewer retinal cells have already been damaged or lost. Genetic testing in the paediatric population is now more important than ever, providing a more accurate diagnosis on a genetic level and offering potential opportunities for therapies at an earlier stage of disease. Recognising the importance of early gene therapy in IRD, several ongoing clinical trials are enrolling paediatric patients.

Gene therapy heralds new era for inherited retinal diseases

As an example, AGTC is enrolling patients as young as 8 years in its ongoing phase 1/2 clinical trial in patients with XLRP and is enrolling patients between 4 and 8 years in its ongoing phase 1/2 clinical trials in patients with achromatopsia due to mutations in the CNGA3 or CNGB3 genes. These trials and the potential near-term inclusion of paediatric patients in other IRD gene therapy trials underscore the importance of referring paediatric patients with IRDs for genetic testing. Eye care professionals who see paediatric patients have a critical role to play in educating these patients and their parents about the availability and potential benefits of IRD genetic testing.

Additionally, physicians who refer patients for testing should ensure that appropriate genetic counselling is available.

Several patients in my practice have been treated with voretigene neparvovec-rzyl and have experienced improvements in visual function, even allowing some to return to normal childhood activities. I am optimistic that additional gene therapies will provide similar benefit to patients with other IRDs. Eye health professionals can help realise the full potential of these therapies by offering and encouraging patients to pursue genetic testing as soon as an IRD or other rare disease is suspected.

Myopia progression can be slowed with multifocal and orthokeratology lenses

Confirmation of an IRD with genetic testing can help patients and physicians make informed decisions about clinical trial opportunities today and future trial and treatment options as additional therapies enter the clinic and the market. Depending on the IRD, the sensitivity of genetic testing can range from around 60% to 90%. Although a negative test does not rule out a genetic dystrophy, it may in some circumstances lead to testing for other causes.

The availability of genetic counselling through the aforementioned testing programmes allows for an accurate interpretation of results along with any additional recommendations. According to an old advertising slogan, “an educated consumer is our best customer,” but in the evolving landscape of IRD gene therapy, an educated physician will be the best care provider.

Mathias is an assistant professor of ophthalmology at the University of Colorado School of Medicine in Aurora.

With at least 24 inherited retinal disease (IRD) clinical trials ongoing in the United States, and additional studies of stem cell therapy in several IRD indications, hope is on the horizon for many patients. 

Paediatric ophthalmologists target inherited retinal diseases

 presents a comprehensive discussion of current knowledge regarding the disease state, raises important questions to be addressed in future research and underscores the idea that AMD is not a single entity but instead represents a disease spectrum with distinct phenotypes that appear to have different underlying risk factors and pathogenic pathways.

 was written by invitation from the journal’s editors and represents joint efforts by an international expert panel organised by Emily Y. Chew, MD, PhD, director of the Division of Epidemiology and Clinical Applications at the National Eye Institute at the National Institutes of Health in Bethesda, Maryland. The paper covers epidemiology; mechanisms/pathophysiology; diagnosis, screening and prevention; management; and quality of life, and it cites 280 references.

Age-related macular degeneration: treatment overview (video)

Monika Fleckenstein, MD, a professor of ophthalmology at John A. Moran Eye Center at the University of Utah in Salt Lake City, is the first author of the work. Although there have been several recent review articles on AMD, Fleckenstein told 

™ that she believes this paper stands out for the depth and breadth of the information it contains.

“Although our paper, which is a review article, does not present new original research, we believe it highlights some important new concepts about AMD and topics for future investigations,” she said.

Ray tracing and IOL modelling in AMD patients (video)

Moreover, Fleckenstein added that her team believes the global overview of AMD provided in their paper will be useful for all ophthalmologists, ophthalmologists in training and physicians in other fields of medicine in addition to anyone with a special interest in AMD.

“We hope that our emphasis on the idea that AMD comprises diverse pathological conditions will be thought-provoking for basic and clinical scientists as they plan new research that ultimately will lead to improved care and better quality of life for patients with AMD,” she added.

Fleckenstein pointed out that when the article was solicited, the journal editors asked that it describe a model of AMD. However, complying with this request challenged the writing group because the exact interactions of pathophysiological events that may culminate in different AMD types remain to be elucidated.

“We know there are different phenotypes and stages in this bucket of AMD, and because of accumulating evidence, we are more and more convinced there are different dominant mechanisms for their development,” Fleckenstein said.

Ang-2/VEGF-A inhibition synergistic effect in DME and AMD (video)

For example, she noted that current information indicates that risk factors for the development of geographic atrophy differ from those associated with progression of the atrophic lesions. Knowledge of these differences is important for investigators, as it indicates a need to focus on different targets for preventive versus therapeutic interventions.

In discussing neovascularisation in AMD, the paper highlights new concepts and terminologies that have emerged thanks to clinicopathological correlations that have been refined through advances in imaging techniques. First, the paper uses the term 

based on the fact that not all neovascularisation in the area of the macula arises from the choroid.

Non-viral gene therapy eases treatment burden in wet AMD

In addition, the article reviews evidence of different types of MNV, some of which seem to protect against AMD progression.

“This latter concept was first put forth decades ago by histopathologists but has only recently gained full attention because newer imaging technologies have enhanced our ability to visualise different subtypes of MNV in vivo,” Fleckenstein said. “Indeed, several studies implementing high-resolution retinal imaging have shown that rates of dry AMD progression differ depending on the presence of certain MNV subtypes.”

Fleckenstein added that the observations may lead to the identification of new therapeutic targets and also argue against interventions that aim to eliminate all MNV.

One goal of developing new consensus terminologies for distinct manifestations of AMD is to provide a complete view of pathological changes that occur in the disease.

Fleckenstein noted, however, that it is a task not easily done. For example, although the term 

recognises the fact that not all AMD-related neovascularisation originates from the choroid, it does not account for the fact that AMD can also be associated with neovascularisation in the peripheral retina.

Brolucizumab for neovascular AMD: Safety guidance and clinician perspectives

“It became clear to me while working on this project that it is not always possible to find all-inclusive terms that also reflect the range of experts’ opinions,” she said. Even if a group comes to a consensus about a particular classification system or preferred term, other specialists in the field may not agree.

“But it is the open-minded discourse that will advance our field,” she noted. “We also have to realise that terminologies are always subject to flux as new information emerges.”

Fleckenstein receives grants from Heidelberg Engineering, Genentech/Roche, Novartis and Optos; personal fees from Bayer, Heidelberg Engineering, Genentech/Roche and Novartis; and nonfinancial support from Carl Zeiss Meditec, Heidelberg Engineering and Optos outside the submitted work.

1. Fleckenstein M, Keenan TDL, Guymer RH et al. Age-related macular degeneration. 

2021;7(1):31. https://doi.org/10.1038/s41572-021-00265-2

2. Fleckenstein M, Mitchell P, Freund KB, Sadda S, Holz FG, Brittain C, Henry EC, Ferrara D. The progression of geographic atrophy secondary to age-related macular degeneration. 

 2018;125(3):369-390. doi: 10.1016/j.ophtha.2017.08.038. Epub 2017 Oct 27. PMID: 29110945

Why investigators are recognising AMD as a disease spectrum rather than a single entity.

Expanding the definition of AMD

Periodic aflibercept (Eylea; Regeneron Pharmaceuticals) treatment for moderate to severe nonproliferative diabetic retinopathy (NPDR) resulted in fewer patients developing PDR or centre-involving diabetic macular oedema (DMO), although no positive effect on visual acuity (VA) was seen, according to Raj K. Maturi, MD, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, who reported the interim 2-year results of the DRCR Retina Network Protocol W study.

“Eyes with moderate to severe NPDR are at high risk for disease progression and development of vision-threatening complications,” Maturi stated, underscoring the importance of determining whether aflibercept prevents development of PDR and centre-involved DMO as well as the potential for a visual benefit at the later 4-year point.

Protocol W is a randomised multicentre clinical trial of adults with type 1 or 2 diabetes and severe NPDR in at least 1 eye. Included patients had no evidence of neovascularisation on fluorescein angiography and a best-corrected VA letter score of 79 or higher, ie Snellen acuity of 20/25 or better. Patients were randomly assigned to receive either 2 mg of periodically administered intravitreous aflibercept or sham injection. Monthly injections were administered for the first 3 visits and followed by injections at months 4, 8 and 12. Before 2 years, injections were administered at each visit, with subsequent treatment with aflibercept only if the diabetic retinopathy exceeded mild NPDR.

Evaluating patients for a retinal disorder (video)

The primary outcome was the cumulative probability of development of PDR or centre-involving DMO with vision loss. Treatment was deferred if the eye had no worse than mild NPDR. Aflibercept was administered in both groups if centre-involving DMO with vision loss or high-risk PDR developed.

A total of 399 eyes of 328 patients were included (mean age, 56 years), all of whom had moderate to severe NPDR. Of these, 200 were randomised to aflibercept and 199 to sham treatment; data from all these patients were included in the primary analysis.

At 2 years, more patients randomised to sham therapy developed DMO or PDR compared with those randomised to aflibercept (44% vs 16%, respectively; adjusted HR, 0.32; P < .001), Maturi reported.

The time to development of PDR was 33% in the sham group and 14% in the aflibercept group. The time to development of DMO was 15% in the sham group and 4% in the aflibercept group. “The criteria for the development of the first PDR and/or DMO [were] met in 35 patients in the aflibercept group and 81 patients in the sham group,” Maturi said.

DMO study shows robust efficacy of intravitreal dexamethasone implant

Most patients in both groups developed neovascularisation of the disc and/or neovascularisation elsewhere, 4 patients in each group developed vitreous haemorrhage and 1 patient in the sham group developed neovascularisation of the iris compared with no patients in the aflibercept group.

VEGF therapy was administered to 3 patients in each group, and focal or grid laser for DMO was administered in 1 patient in the sham group.

Analysis conducted to determine a correlation between the baseline NPDR severity and development of DMO or PDR indicated a definite relationship based on more severe disease.

“Among patients with the lowest levels of NPDR, only 3% in the aflibercept group went on to develop DMO or PDR compared with 24% in the sham group,” Maturi said. “Among patients with severe NPDR, 36% went on to develop DMO or PDR in the aflibercept group, and 68% did so in the sham group despite regular treatments.”

Analysis of the change in the severity of diabetic retinopathy at 2 years showed that 5% of patients in the aflibercept group had a 2-step worsening of disease compared with 12% in the sham group. Regarding improvement, 45% of patients in the aflibercept group had a 2-step or greater improvement compared with 14% in the sham group.

Diabetes and DR: Making progress in the global epidemic

Comparison of the 2 treatment groups showed almost no difference in adjusted mean VA over 2 years. The central subfield thickness improved slightly and nonsignificantly by –6 microns in the aflibercept group and –1 micron in the sham group.

About 5 injections of aflibercept were administered for DMO and 0.3 in the sham group; over 2 years, the aflibercept patients received 8 injections and the sham-treated patients received 1.1 injections.

Adverse events associated with aflibercept included 3 cases of endophthalmitis, 2 of retinal detachment, 13 of IOP spikes of 10 mm Hg or higher and 8 of IOP elevations of 30 mm Hg or higher. In the sham group, 2 patients had retinal detachments, 12 had IOP spikes of 10 mm Hg or higher and 3 had IOP spikes of 30 mm Hg or higher.

Common types of retinal disorders explored (video)

Hypertension was the systemic event seen in more patients, with 18 in the aflibercept cohort and 13 in the sham group.

The major study findings indicated that among eyes with moderate to severe NPDR, the proportion that developed PDR or centre-involving DMO was lower with periodic aflibercept treatments compared with sham treatment through the 2-year point. Preventive treatment with aflibercept did not confer a VA benefit compared with anti-VEGF initiated after PDR or DMO development.

Maturi pointed out that this 4-year study may be important to determine whether preventing PDR and centre-involved DMO improves the long-term outcomes.

This article was adapted from Maturi’s presentation at the Association for Research in Vision and Ophthalmology 2021 virtual annual meeting. He has no financial interest in this subject matter.

The proportion of eyes that developed PDR or centre-involving DMO was lower with periodic aflibercept treatments compared with sham treatment through the 2-year point.

Modern Retina Europe Summer 2021

Inner fluid volume and its role in macular hole repair

Using FLIO to monitor AMD progression

Sustained-release anti-inflammatory therapy proves valuable in NIU

Paediatric ophthalmologists target inherited retinal diseases

Expanding the definition of AMD

Study evaluates periodic aflibercept injections in NPDR treatment