Cassie A. Ludwig, MD, MS
Vitreoretinal Surgery Fellow
Massachusetts Eye and Ear
Photos Courtesy of Karen Wai, MD
The 2021 Debates at the American Academy of Ophthalmology moderated by Drs. Vaidehi Shradha Dedania, MD, Tarek S. Hassan, MD, and John S. Pollack, MD covered four hot topics in the field of vitreoretinal surgery: telemedicine screening for diabetic retinopathy, the risk/benefit ratio for use of brolicizumab, the use of anti-vascular endothelial growth factor (VEGF) therapy for severe non-proliferative diabetic retinopathy (NPDR) and the best surgical technique for large refractory macular holes.
Telemedicine Screening for Diabetic Retinopathy
Dr. Jennifer I. Lim, MD from the University of Chicago at Illinois argued that telemedicine screening is ready to go, noting that telemedicine screening addresses the diabetic retinopathy burden, is efficient and effective, and has been automated using AI algorithms approved by the FDA. Dr. Lim cited the growing diabetic retinopathy screening burden globally with 415 million diabetics in 2015, predicted to rise to 642 million diabetics by 2040. She noted that telemedicine screening addresses the shortage of eyecare providers and addresses the mismatch of providers and patients (rural and socioeconomically disadvantaged) which can lead to disparities of care. Dr. Lim then reviewed the efficiency of telemedicine screening which was found to increase screening rate from 29.9% to 47.7% (de Carvalho et al. 2020). She continued that while only 30-50% of diabetic patients see an eyecare provider, 88% visit their PCP at least once a year, providing an opportunity for point of care screening. This was studied at the Wills Eye Hospital where 9,946 patients were screened at a PCP visit, 16.6% of whom were found to have diabetic retinopathy in at least one eye and 25% with other eye disease (Gao et al. 2019). Similarly, telemedicine screening was implemented in remote medical clinics on Native American reservations and urban family practice clinics and diabetic retinopathy was found in 12.6% and 29.6% of eyes respectively (Chin et al. 2013). Lastly, Dr. Lin noted that telemedicine systems allow for physician treatment rather than disease screening with high sensitivity and specificity of current FDA approved AI systems IDxDR (87.2% sensitivity, 90.7% specificity) and EyeArt (96% sensitivity, 88% specificity).
Dr. Christina Y. Weng, MD, MBA from the Baylor College of Medicine-Cullen Eye Institute agreed with Dr. Lim that telemedicine screening is valuable, but countered its readiness for prime time, comparing its premature launch to that of startup Astra’s third failed rocket test launch in August. Dr. Weng went on to note that telemedicine screening has a ways to go because of its suboptimal detection of diabetic macular edema, prohibitive socioeconomics, and issues with post-screening compliance. While telemedicine may allow for screening of retinopathy, it may miss diabetic macular edema which has an estimated prevalence of over 500,000 individuals in the US (Cohen et al. 2016). She went on to state that if OCT were to be integrated, the cost would rise, worsening the next hurdle for telemedicine screening. Non-AI based screening costs $24.38 to $48.00 per patient while new devices for imaging cost $18,000 (Garoon et al. 2018, Phan et al. 2014, Li et al. 2012). Dr. Weng contended that each read costs $31.06 making it such that reimbursement rates barely cover associated costs. Lastly, Dr. Weng emphasized that over a 4-year period, only 52.4% of those in the Harris Health System program referred for an in-clinic exam actually attended their exam (Date et al. 2019) raising concern for the overall effectiveness of the screening method.
The Audience Voted: Has a Ways to Go (Christina Y Weng, MD, MBA)
The Risk/Benefit Ratio for Brolicizumab
Dr. Rishi P. Singh, MD from Cole Eye Institute, The Cleveland Clinic contended that the Phase 3 studies HAWK and HARRIER validated its equivalence in visual acuity to aflibercept. Additionally he pointed out its superiority in regard to CSFT including SRF and IRF in Phase 3 studies. Furthermore, half of patients were on q12 dosing by the end of year one. Dr. Singh acknowledged the primary issues of retinal vasculitis and retinal occlusive disease that have been validated in the IRIS and KomodoHealth databases. He further acknowledged that the MERLIN study which dosed on a q4 interval was halted and that brolucizumab is only approved for use every 2 months by the FDA. However, per Dr. Singh, in certain cases, the risk benefit ratio is acceptable – in patients with early residual fluid and high frequency of treatment. However, he again affirmed that brolucizumab is contraindicated in those with prior intraocular inflammation events.
Dr. Paul Hahn, MD, PhD from NJRetina responded by pointing out that HAWK and HARRIER demonstrated the non-inferiority of change in visual acuity as the primary outcome but that superiority in drying the macula was a secondary outcome. Dr. Hahn continued to underscore the high incidence of occlusive retinal vasculitis with brolicizumab at 1:200 with 1:5 risk of subsequent devastating vision loss over 6 lines. He stated that while Novartis was quick to commission a safety committee and identify this problem, no new relevant information has come out in 2021 that would help mitigate the risk benefit profile of using brolicizumab. He acknowledged the possibility of benefits for those using a high frequency of alternative anti-VEGF agents, but stated that with pipeline therapies offering improved efficacy, longer duration and consistent safety, the risks for giving brolicizumab continue to outweigh the benefits. In closing, he cited the 2021 ASRS PAT survey in which two thirds of retina specialists stated that they would not offer brolicizumab.
The Audience Voted: Is Not Acceptable (Dr. Paul Hahn, MD, PhD)
The Best Treatment for Severe Nonproliferative Diabetic Retinopathy without Macular Edema
Dr. Diana V. Do, MD from Byers Eye Institute, Stanford University School of Medicine argued for use of regular anti-VEGF therapy for severe NPDR. Dr. Do began by describing the similarity between diabetic retinopathy and coronary artery and coronary vascular disease – all chronic conditions that, Dr. Do contends, require physicians to be proactive rather than reactive. Dr. Do stated that observing severe NPDR leads to 50% of these eyes to progress to PDR within 1 year (Bakri et al. 2019). RIDE, RISE and PANORAMA all demonstrate that anti-VEGF therapies reverse retinopathy, and that these effects could be achieved with q16 week dosing. The number needed to treat to prevent vision threatening complications in PANORAMA was 3 patients. Lastly, there was a statistically significant benefit with treatment as compared to observation when we look at the area under the curve in the PANORAMA study as well. Dr. Do ended by recommending we be proactive and offer this treatment to our patients before we watch them worsen.
Dr. Ramin Tadayoni, MD, PhD from Université de Paris argued instead for regular observation of patients with severe NPDR. He cited Protocol W which found that preventative treatment did not confer a BCVA benefit compared with observation and aflibercept only after PDR develops. Dr. Tadayoni then noted that regular observation and photography every 3 months is less invasive and cheaper than anti-VEGF therapy. Per Dr. Tadayoni, in PDR, use of anti-VEGF therapy was found to be more than $700,000 per quality-adjusted life year more expensive than use of PRP. Dr. Tadayoni described studies he performed in which he looked at UWF-FA and UWF-OCTA and did not find any improvement in perfusion after anti-VEGF therapy, further defending observation over treatment in the case of severe NPDR.
The Audience Voted: Regular Observation (Ramin Tadayoni, MD, PhD)
The Best Procedure for Large Refractory Macular Hole
Dr. Dilraj S. Grewal, MD from Duke Eye Center began by describing the motivation for the first autologous retinal transplant (ART) graft – a -15D myope with an over 1000 micron macular hole who presented to Dr. Tamer Mahmoud after having undergone multiple prior surgeries. The technique includes use of a graft 1.2 to 1.5x the size of the macular hole harvested superior to superotemporal. Light diathermy is applied to the vessels surrounding the harvest site, the graft is excised with vertical scissors to leave a graft hinge, and PFC is instilled to cover the macular hole and donor site. The graft hinge is severed and maneuvered over the macular hole. This can be followed by a PFC tamponade for 2 weeks, silicone oil for 1 month or a gas tamponade. Per Dr. Grewal, the advantage is neural integration that takes advantage of synaptic plasticity and ectopic synaptogenesis leading to structural and functional rehabilitation. OCT post-operatively defends this theory, showing reconstitution of EZ alignment of neurosensory layers. Dr. Grewal described evidence of secondary vascularization and reperfusion of the graft on OCTA. Graft dislocation is <5% and it can be readjusted under PFO or a new graft can be harvested. Dr. Grewal noted that ART can be used for chronic primary large macular holes, those associated with retinal detachment and other pathologies including optic disc coloboma and Alport syndrome. He emphasized an over 80% closure rate and at least one third of eyes with significant improvement in vision defined as greater than 3 or more lines.
Dr. Carsten H. Meyer, MD from Retina Department of the Federal University of Sao Paulo described the reasoning behind perifoveal hydrodissection – firm adhesions between the RPE and retina that may prevent closure even after complete ILM peel. To break these adhesions, Dr. Meyer advocated for subretinal fluid application to stretch and release the retina for closure. Dr. Meyer described his evaluation of 152 cases of persistent macular holes with an outer width of 1121 +/- 482 um performed by 44 surgeons in 31 centers in 13 countries. Average duration was 16.8 months. Overall closure was 83.6% (152/127) with a mean gain of 3.9 lines of vision (SD 3.7). Idiopathic macular holes had a better outcome (89.9%) compared with secondary macular holes (myopia, trauma, vasculopathies) (60.6%). Dr. Meyer noted that though most macular holes close after vitrectomy with ILM peel, persisting macular holes may require perifoveal hydrodissection to release firm perifoveal adhesions.
The Audience Voted: Perifoveal Hydrodissection (Dr. Carsten H. Meyer, MD)