Results of the OASIS Trial ERG Substudy
To explore a possible association between full-field electroretinograms with vitreomacular adhesion resolution and best-corrected visual acuity as part of the prospective, randomized, double-masked, sham-controlled Ocriplasmin for Treatment for Symptomatic Vitreomacular Adhesion Including Macular Hole (OASIS) trial studying ocriplasmin.
The ERG substudy enrolled 62 of 220 OASIS subjects (randomized 2:1) and analyzed full-field electroretinograms and their association with both vitreomacular adhesion resolution and best-corrected visual acuity from baseline through Month 24. Electroretinogram reductions were defined as acute full-field electroretinogram reductions in amplitude of $40% from baseline occurring at postinjection Day 7 or Day 28.
In the ocriplasmin group, 16/40 (40%) subjects developed ERG reductions, compared to 1/21 (4.8%) in the sham group; 13/16 (81.3%) and 1/1 (100%) resolved by study end, respectively. A total of 11/16 (68.8%) ocriplasmin-treated subjects with ERG reductions achieved vitreomacular adhesion resolution, compared to those without (9/24, 37.5%). The ocriplasmin-treated subjects with ERG reductions also gained more letters on average (11.3 vs. 9.3 letters) from baseline and had a difference of 6.7 letters in mean bestcorrected visual acuity by study end compared to those without ERG reductions.
Ocriplasmin-treated subjects with ERG reductions had a higher rate of vitreomacular adhesion resolution and showed better visual improvement than their counterparts without ERG reductions or sham subjects by study end.
RETINA 38:364–378, 2018
Full Paper: Evaluation of Full-Field Electroretinogram Reductions After Ocriplasmin Treatment
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Recent press releases regarding the potential adverse effects of aspirin on macular degeneration have caused patients with age-related macular degeneration (AMD) to discontinue their aspirin use without consulting their physician.1,2 There are many benefits to aspirin use, and therefore many reasons patients should continue taking the recommended aspirin dose prescribed by their primary physician or cardiologists. As with any treatment, it is important to weigh the risk/benefit ratio of aspirin use, especially in generally elderly and high-risk populations. The benefits of aspirin have long been well documented and highly recommended for the prevention and treatment of cardiovascular diseases (CVDs), such as myocardial infarction, stroke, and death. The recent retrospective epidemiological eye studies suggesting that aspirin use may exacerbate macular degeneration are based on three limited studies, while the benefits of aspirin use for macular degeneration patients have been suggested in larger studies, including Age-Related Eye Disease Study (AREDS), the Physicians Health Study (PHS), Women’s Health Study (WHS).1–4 Therefore, the data regarding the effects of aspirin on AMD are conflicting and inconclusive.
Full Paper: Macular Degeneration and Aspirin Use
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A 77-year-old woman with exudative macular degeneration underwent bilateral intravitreal injections of “stem cells” at a clinic in Georgia. One month and 3 months after injection, she developed retinal detachments in the left and right eyes, respectively. Increased awareness within the medical community of such poor outcomes is critical so that clinics offering untested practices that have been shown to be potentially harmful to patients can be identified and brought under U.S. Food and Drug Administration oversight.
Enthusiasm for stem cell treatment has given rise to numerous clinics in the United States offering unproven “stem cell” therapies without the oversight of the U.S. Food and Drug Administration (FDA). Though current FDA-regulated clinical trials are ongoing to evaluate the use of stem cell technology, unproven and unregulated “stem cell” therapies are already being offered to patients in hundreds of clinics in the United States. In June 2016, the American Academy of Ophthalmology published a clinical statement warning that unproven “stem cell” therapies “require further scientific evaluation to assure their safety and effectiveness to the public in well-conducted clinical trials under the aegis of the FDA.”1 Here, we describe a case of delayed retinal detachment with poor visual acuity and anatomical outcomes following bilateral intravitreal injection of autologous adipose tissue-derived “stem cell” therapy in a clinic in Georgia performed without FDA oversight.
Full Paper: Bilateral Retinal Detachments After Intravitreal Injection of Adipose-Derived ‘Stem Cells’ in a Patient With Exudative Macular Degeneration
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New and unique physiologic and pathologic systemic and neuro-ocular responses have been documented in astronauts during and after long-duration space flight. Although the precise cause remains unknown, space flight–associated neuro-ocular syndrome (SANS) has been adopted as an appropriate descriptive term. The Space Medicine Operations Division of the US National Aeronautics and Space Administration (NASA) has documented the variable ccurrence of SANS in astronauts returning from long-duration space flight on the International Space Station. These clinical findings have included unilateral and bilateral optic disc edema, globe flattening, choroidal and retinal folds, hyperopic refractive error shifts, and nerve fiber layer infarcts. The clinical findings of SANS have been correlated with structural changes on intraorbital and intracranial magnetic resonance imaging and in-flight and terrestrial ultrasonographic studies and ocular optical coherence tomography. Further study of SANS is ongoing for consideration of future manned missions to space, including a return trip to the moon or Mars.
Full Paper: Space Flight Associated Neuro-Ocular Syndrome
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Table 1. “Age-Related Macular Degeneration Clinical Trials With Oral Medications”
(Retinalphysician.com | April 2017)
Full Paper: Age-Related Macular Degeneration Clinical Trials With Oral Medications Table
Arecent Diabetic Retinopathy Clinical Research Network (DRCR.net) comparative effectiveness trial found that for patients with diabetic macular edema (DME) and approximate Snellen equivalent baseline visual acuity (VA) of 20/50 or worse aflibercept produced greater mean VA gains at 1 year than bevacizumab or ranibizumab. In contrast, no difference in mean VA improvement was identified for patients with baseline VAs of 20/32 to 20/40.1
These agents also vary substantially in cost. O nthe basis of 2015 wholesale acquisition costs, aflibercept (2.0 mg) costs $1850,2 ranibizumab (0.3mg) costs $1170,2 and bevacizumab repackaged at compounding pharmacies into syringes for ophthalmologic use containing 1.25mg of bevacizumab costs approximately $6 0per dose.3 Considering that these medicines may be given 9 to 11 times in the first year of treatment1 and, on average, 17 times during 5 years,4 total costs can be substantial. In 2010, when these intravitreous agents were being used predominantly for age-related macular degeneration, ophthalmologic use of anti–vascular endothelial growth factor (VEGF)therapy cost approximately $2 billion or one-sixth of the entire Medicare Part B drug budget.3 In 2013, Medicare Part B expenditures for aflibercept and ranibizumab alone totaled $2.5 billion.5 Given these costs, the DRCR.net investigators believed it was important to analyze the relative cost-effectiveness of treating DME using each agent.
Full Paper: Cost-effectiveness of Aflibercept, Bevacizumab, and Ranibizumab for Diabetic Macular Edema Treatment
There is a subset of eyes with neovascular age-related macular degeneration (AMD) that have persistent exudation despite fixed-interval intravitreous anti–vascular endothelial growth factor (VEGF) injections.
To evaluate the effect of topical dorzolamide hydrochloride–timolol maleate on anatomic and functional outcomes in eyes with neovascular AMD and incomplete response to anti-VEGF therapy.
Design, Setting, and Participants
An exploratory, prospective single-arm interventional study at a tertiary referral academic private practice. Patients with neovascular AMD and persistent macular edema despite fixed-interval intravitreous anti-VEGF therapy were enrolled. Baseline spectral-domain optical coherence tomography and clinical data, including visual acuity and intraocular pressure, were obtained at enrollment and from one visit before enrollment. The study was performed at the Retina Service of Wills Eye Hospital and the offices of Mid Atlantic Retina from February 1, 2015, through September 30, 2015. Patients were followed up for at least 2 visits after enrollment. Central subfield thickness, maximum subretinal fluid height, and maximum pigment epithelial detachment height from spectral-domain optical coherence tomography were recorded at each visit. INTERVENTIONS Enrolled eyes received a regimen of topical dorzolamide-timolol twice daily and continued to receive the same intravitreous anti-VEGF therapy at the same interval as received before enrollment for the duration of the study.
Main Outcomes and Measures
Change in central subfield thicknesswas the primary outcome measure. Changes in maximum subretinal fluid height, maximum pigment epithelial detachment height, and visual acuity were the secondary outcome measures.
Ten patients (10 eyes) completed the study. The mean age of the patients was 78.2 years (age range, 65-91 years), and 6 were male. Eight eyes received intravitreous aflibercept, and 2 eyes received intravitreous ranibizumab. All study eyes had been receiving long-term anti-VEGF therapy with the same medication before study enrollment for a mean of 21.9 injections. The mean central subfield thickness decreased from 419.7 μmat enrollment to 334.1 μm at the final visit (P = .01). The mean maximum subretinal fluid height decreased from 126.6 μmat enrollment to 49.5 μm at the final visit (P = .02). The mean maximum pigment epithelial detachment height decreased from 277.4 μmat enrollment to 239.9 μmat the final visit (P = .12). The mean logMAR visual acuity were 0.54 at enrollment and 0.48 at the final visit (P = .60).
Conclusions and Relevance
These data suggest that topical dorzolamide-timolol may reduce central subfield thickness and subretinal fluid in eyes with persistent exudation despite consistent, fixed-interval intravitreous anti-VEGF treatment for neovascular AMD.
Full Paper: Topical Dorzolamide-Timolol With Intravitreous Anti–Vascular Endothelial Growth Factor for Neovascular Age-Related Macular Degeneration
Diabetic Macular Edema (DME) is the leading cause of visual impairment in patients with diabetic retinopathy.1 In 2010, approximately 20.6 million out of a projected 92.6 million adults with diabetic retinopathy worldwide were estimated to have concurrent DME.2 This global healthcare burden will likely continue to increase at alarming rates, as some models estimate the number of diabetics will double by the year 2030.3
With the Early Treatment Diabetic Retinopathy Study (ETDRS) in the 1980s,4 macular laser photocoagulation became the mainstay of DME management, and it remained the standard of care in the decades that followed. The advent of intravitreal pharmacotherapy agents, primarily driven by the class of vascular endothelial growth factor (VEGF) inhibitors, has since revolutionized how this condition is treated. Validated through the RISE and RIDE phase 3 clinical trials,5 ranibizumab (Lucentis; Genentech, South San Francisco, California, USA) became the first VEGF inhibitor approved by the Food & Drug Administration (FDA) for this indication in 2012.
While off-label, bevacizumab (Avastin; Genentech) has been evaluated through smaller trials, such as the BOLT study.6 Most recently, aflibercept (Eylea; Regeneron, Tarrytown, New York) gained FDA approval to treat DME in July 2014 with the VIVID and VISTA phase 3 clinical trials.7,8
While there is ample evidence supporting the safety and efficacy of the 3 anti-VEGF agents in the management of DME, a head-to-head comparison only recently became available when the Diabetic Retinopathy Clinical Research Network (DRCR) published the 1-year outcomes of its Comparative Effectiveness Study of Intravitreal Aflibercept, Bevacizumab, and Ranibizumab for DME (Protocol T).9 The results demonstrated that when baseline visual acuity (VA) loss was mild (›20/ 40), there was no clinical difference between the 3 medications. However, when the initial acuity loss was more severe (‹20/50), a greater visual benefit was derived from aflibercept.9
Since the FDA approval of aflibercept for DME, and in light of Protocol T’s findings, many retinal specialists are converting eyes from ranibizumab or bevacizumab to aflibercept with the goal of optimizing treatment outcomes, particularly in cases of refractory DME. In the current study, we evaluated the short-term functional and anatomic responses of patients with persistent DME after multiple previous anti-VEGF injections that were converted to aflibercept therapy.
Full Paper: Conversion to Aflibercept After Prior Anti-VEGF Therapy for Persistent Diabetic Macular Edema
Age-related macular degeneration is a very common condition that is caused by a complex interplay of genetic and environmental factors. It is likely that, in the future, genetic testing will allow physicians to achieve better clinical outcomes by administering specific treatments to patients based on their genotypes. However, improved outcomes for genotyped patients have not yet been demonstrated in a prospective clinical trial, and as a result, the costs and risks of routine genetic testing currently outweigh the benefits for patients with age-related macular degeneration.
Full Paper: Genetic Testing for Age-Related Macular Degeneration Not Indicated Now
For the management of retinal disease, the use of intravitreous injections of anti–vascular endothelial growth factor has increased. Recent reports have suggested that this therapymay cause sustained elevation of intraocular pressure (IOP) and may potentially increase the risk of glaucoma for patients with retinal disease. OBJECTIVE To assess the risk of sustained IOP elevation or the need for IOP-lowering treatments for eyes with diabetic macular edema following repeated intravitreous injections of ranibizumab.
Design, Setting, and Participants
An exploratory analysiswas conducted within a Diabetic Retinopathy Clinical Research Network randomized clinical trial. Study enrollment dates were from March 20, 2007, to December 17, 2008. Of 582 eyes (of 486 participants) with center-involved diabetic macular edema and no preexisting open-angle glaucoma, 260 were randomly assigned to receive a sham injection plus focal/grid laser treatment, and 322 were randomly assigned to receive ranibizumab plus deferred or prompt focal/grid laser treatment.
Main Outcomes and Measures
The cumulative probability of sustained IOP elevation, defined as IOP of at least 22mmHg and an increase of at least 6mmHg from baseline at 2 consecutive visits, or the initiation or augmentation of ocular hypotensive therapy, through 3 years of follow-up.
The mean (SD) baseline IOP in both treatment groups was 16 (3)mmHg (range, 5-24mmHg). The cumulative probability of sustained IOP elevation or of initiation or augmentation of ocular hypotensive therapy by 3 years, after repeated ranibizumab injections, was 9.5%for the participants who received ranibizumab plus prompt or deferred focal/grid laser treatment vs 3.4%for the participants who received a sham injection plus focal/grid laser treatment (difference, 6.1%[99%CI, −0.2%to 12.3%]; hazard ratio, 2.9 [99% CI, 1.0-7.9]; P = .01). The distribution of IOP and the change in IOP from baseline at each visit through 3 years were similar in each group.
Conclusions and Relevance
In eyes with center-involved diabetic macular edema and no prior open-angle glaucoma, repeated intravitreous injections of ranibizumab may increase the risk of sustained IOP elevation or the need for ocular hypotensive treatment. Clinicians should be aware of this risk and should consider this information when following up with patients who have received intravitreous injections of anti–vascular endothelial growth factor for the treatment of diabetic macular edema.
Full Paper: Repeated Intravitreous Ranibizumab Injections