Anti-VEGF Pharmaceutical Prior Authorization in Retina Practices.

Importance: Anti-vascular endothelial growth factor (VEGF) intravitreal injections, a mainstay of treatment for many retinal diseases to optimize visual outcomes, have been included in prior authorization (PA) initiatives. However, if clinicians are extremely accurate in their use of anti-VEGF medications, such administrative burdens may need reconsideration. Objective: To quantify PA for anti-VEGF medications (aflibercept, ranibizumab, and bevacizumab) that were approved and determine associated administrative burdens experienced by retina practices. Design, Setting, and Participants: Prospective multicenter quality improvement study conducted from January 2022 through June 2022, and participants were 9 private retina practices across the US. Main Outcomes and Measures: Overall rate of approval of PA requests, reasons for requesting PA, and overall rate of delay of care resulting from PA procedures. Results: In total, 2365 PA requests were recorded, 2225 of which met inclusion criteria. Overall, 2140 (96.2%) requests were approved. The most common reason for requesting PA, at 64% (1423 of 2225 requests), was reauthorization for a previously utilized medication. Of the 2140 approvals, 59.6% (1277) resulted in a delay in care greater than 24 hours, and 40% (863) were given on the date of service. In a granular analysis of a subset of delayed approvals, 23.9% (173 of 725) were approved within 1 day, 15.9% (115 of 725) were approved within 2 to 3 days, 21.5% (156 of 725) were approved within 4 to 7 days, 26.3% (191 of 725) were approved within 8 to 31 days, and 12.4% (90 of 725) were approved within more than 31 days. Overall, PA denial for step therapy was 2.9% (65 of 2225) of requests and uncovered diagnoses was 0.9% (20 of 2225) of requests. The median staff time spent to obtain a single PA was 100 (range, 0-200) minutes. Conclusions and Relevance: In this study, PA requests were almost always approved but led to a delay in patient care in most patients. The current study suggests that the PA process may not be effective for retina specialists if these results can be generalized to other practices in the US and if less burdensome and less costly approaches could result in similar approval rates. Potential short-term solutions may include eliminating the PA process for bevacizumab and reauthorizations for established patients.

Identification of a Novel Mucin Gene HCG22 Associated With Steroid-Induced Ocular Hypertension.

PURPOSE: The pathophysiology of ocular hypertension (OH) leading to primary open-angle glaucoma shares many features with a secondary form of OH caused by treatment with glucocorticoids, but also exhibits distinct differences. In this study, a pharmacogenomics approach was taken to discover candidate genes for this disorder. METHODS: A genome-wide association study was performed, followed by an independent candidate gene study, using a cohort enrolled from patients treated with off-label intravitreal triamcinolone, and handling change in IOP as a quantitative trait. RESULTS: An intergenic quantitative trait locus (QTL) was identified at chromosome 6p21.33 near the 5' end of HCG22 that attained the accepted statistical threshold for genome-level significance. The HCG22 transcript, encoding a novel mucin protein, was expressed in trabecular meshwork cells, and expression was stimulated by IL-1, and inhibited by triamcinolone acetate and TGF-ß. Bioinformatic analysis defined the QTL as an approximately 4 kilobase (kb) linkage disequilibrium block containing 10 common single nucleotide polymorphisms (SNPs). Four of these SNPs were identified in the National Center for Biotechnology Information (NCBI) GTEx eQTL browser as modifiers of HCG22 expression. Most are predicted to disrupt or improve motifs for transcription factor binding, the most relevant being disruption of the glucocorticoid receptor binding motif. A second QTL was identified within the predicted signal peptide of the HCG22 encoded protein that could affect its secretion. Translation, O-glycosylation, and secretion of the predicted HCG22 protein was verified in cultured trabecular meshwork cells. CONCLUSIONS: Identification of two independent QTLs that could affect expression of the HCG22 mucin gene product via two different mechanisms (transcription or secretion) is highly suggestive of a role in steroid-induced OH.

Delayed- versus acute-onset endophthalmitis after cataract surgery.

PURPOSE: To report a large consecutive case series of patients who developed delayed-onset and acute-onset endophthalmitis after cataract surgery. DESIGN: Retrospective consecutive case series. METHODS: The current study is a retrospective consecutive case series of patients treated between January 2000 and December 2009 for culture-proven endophthalmitis after cataract surgery. The study defined 2 groups after cataract surgery: acute-onset endophthalmitis (≤6 weeks after surgery) and delayed-onset endophthalmitis (>6 weeks after surgery). RESULTS: A total of 118 patients met study criteria; cases included 26 delayed-onset cases and 92 acute-onset cases. The following clinical features and outcomes occurred in delayed- vs acute-onset cases: 1) the presenting visual acuity was ≤5/200 in 31% vs 89%; 2) hypopyon was found in 46% vs 80%; 3) the most frequent isolate was Propionibacterium acnes (11/26) vs coagulase-negative Staphylococcus (57/92); and 4) patients with the most frequent isolate achieved a visual outcome of ≥20/100 in 91% vs 56%. In delayed-onset cases, the intraocular lens was removed or exchanged in 19 of 26 cases (73%). Of these 19 cases, 13 achieved a visual outcome of ≥20/100. CONCLUSIONS: Patients with delayed-onset endophthalmitis generally presented with better initial visual acuities, had a lower frequency of hypopyon, and had better visual outcomes compared to acute-onset patients. Propionibacterium acnes and coagulase-negative Staphylococcus species were the most common organisms cultured in delayed- and acute-onset categories, respectively, and were associated with the best visual acuity outcomes in each group.

Endophthalmitis after intravitreal vascular [corrected] endothelial growth factor antagonists: a six-year experience at a university referral center.

PURPOSE: To assess the rate of infectious endophthalmitis and to describe the clinical and microbiological features of eyes that develop clinically suspected endophthalmitis after an intravitreal injection of vascular endothelial growth factor antagonists. METHODS: The medical records of patients undergoing intravitreal injections of anti-vascular endothelial growth factor agents from January 1, 2005, through December 31, 2010, at a single university referral center and associated satellite clinics were retrospectively analyzed to determine the rate of infectious endophthalmitis after intravitreal anti-vascular endothelial growth factor injections. RESULTS: Twelve cases (11 patients) of clinically suspected endophthalmitis were identified after a total of 60,322 injections (0.02%; 95% confidence interval, 0.0114%-0.0348%). Of the 12 cases, 11 presented within 3 days of the injection. Of the 7 culture-positive cases, 5 were because of Streptococcus species. In 4 of the 5 Streptococcus cases, final visual acuity was hand motions or worse. The rate of clinically suspected endophthalmitis was 0.018% after bevacizumab and 0.027% after ranibizumab injections. CONCLUSION: A very low rate of endophthalmitis after intravitreal injections of anti-vascular endothelial growth factor agents was observed. Patients typically presented within 3 days of injection. Streptococcus species was the most common bacteria isolated, and it was generally associated with poor visual outcomes.

The comparison of clinical outcomes of endophthalmitis from fluoroquinolone-resistant and susceptible bacteria.

PURPOSE: To identify patients who developed acute-onset endophthalmitis after clear corneal cataract surgery, and to compare treatment outcomes between cases caused by fluoroquinolone susceptible organisms versus fluoroquinolone resistant organisms. DESIGN: Retrospective case series. METHODS: Patients who developed endophthalmitis within six weeks of cataract surgery, and were treated between January 1996 and December 2008 at Bascom Palmer Eye Institute in Miami, Florida, were identified retrospectively. Clinical features, organisms cultured, and visual acuity outcomes were evaluated. RESULTS: A total of 97 patients met study criteria, and 37 (38%) demonstrated in vitro fluoroquinolone resistance. All fluoroquinolone resistant endophthalmitis in the study was caused by either Staphylococcus epidermidis (n = 32) or Staphylococcus aureus (n = 5). Presenting clinical features were similar between fluoroquinolone resistant and fluoroquinolone susceptible groups. Final visual acuity was >/=20/40 in 49% of fluoroquinolone-resistant cases and 42% of fluoroquinolone-susceptible cases. All fluoroquinolone-resistant isolates were susceptible to vancomycin. CONCLUSION: In the current study, approximately one-third of isolates were resistant to fluoroquinolones. There was no significant difference in clinical outcomes in this study, regardless of fluoroquinolone susceptibility.

A variable-dosing regimen with intravitreal ranibizumab for neovascular age-related macular degeneration: year 2 of the PrONTO Study.

PURPOSE: To assess the long-term efficacy of a variable-dosing regimen with ranibizumab in the Prospective Optical Coherence Tomography (OCT) Imaging of Patients with Neovascular Age-Related Macular Degeneration (AMD) Treated with intraOcular Ranibizumab (PrONTO) Study, patients were followed for 2 years. DESIGN: A 2-year prospective, uncontrolled, variable-dosing regimen with intravitreal ranibizumab based on OCT. METHODS: In this open-label, prospective, single-center, uncontrolled clinical study, AMD patients with neovascularization involving the central fovea and a central retinal thickness (CRT) of at least 300 microm as measured by OCT were enrolled to receive 3 consecutive monthly intravitreal injections of ranibizumab (0.5 mg) [Lucentis; Genentech Inc, South San Francisco, California, USA]. During the first year, retreatment with ranibizumab was performed at each monthly visit if any criterion was fulfilled such as an increase in OCT-CRT of at least 100 microm or a loss of 5 letters or more. During the second year, the retreatment criteria were amended to include retreatment if any qualitative increase in the amount of fluid was detected using OCT. RESULTS: Forty patients were enrolled and 37 completed the 2-year study. At month 24, the mean visual acuity (VA) improved by 11.1 letters (P < .001) and the OCT-CRT decreased by 212 microm (P < .001). VA improved by 15 letters or more in 43% of patients. These VA and OCT outcomes were achieved with an average of 9.9 injections over 24 months. CONCLUSIONS: The PrONTO Study using an OCT-guided variable-dosing regimen with intravitreal ranibizumab resulted in VA outcomes comparable with the outcomes from the phase III clinical studies, but fewer intravitreal injections were required.

Spectral domain optical coherence tomography for proliferative diabetic retinopathy with subhyaloid hemorrhage.

A prototype 6-microm axial resolution spectral domain optical coherence tomography (SD-OCT) device was used to image the retina of a patient with uncontrolled diabetes mellitus who had proliferative diabetic retinopathy with subhyaloid hemorrhage. A raster scan pattern with 128 B-scans covering a 6 X 6 X 2-mm volume of the retina was obtained. SD-OCT showed the presence of blood localized between the internal limiting membrane and the posterior hyaloid face and allowed visualization of the cross sectional retinal architecture and the vitreoretinal interface at different horizontal levels that could be registered with the color fundus photograph. SD-OCT provided useful information about the relationship of the hemorrhage to the posterior hyaloid and the retina.

Macular thickness measurements in normal eyes using spectral domain optical coherence tomography.

BACKGROUND AND OBJECTIVE: Knowledge of the macular thickness in a normal population is important for the evaluation of pathological macular change. The purpose of this study was to define and measure macular thickness in normal eyes using spectral domain optical coherence tomography (OCT). PATIENTS AND METHODS: Fifty eyes from 50 normal subjects (29 men and 21 women, aged 22 to 68 years) were scanned with a prototype Cirrus HD-OCT system (5 microm axial resolution) (Carl Zeiss Meditec, Inc.). The proprietary Cirrus segmentation algorithm was used to produce retinal thickness maps, which were then averaged over 9 regions defined by a circular target centered at the true fovea location. The macular thickness of 13 subjects scanned with both HD-OCT and StratusOCT were compared. RESULTS: After centering the fovea, the mean and standard deviation values for retinal thickness measurements were calculated point wise and averaged on standard regions. For patients scanned with both systems, the thickness measurements from HD-OCT were approximately 50 microm larger than those from StratusOCT. The difference between the two measurements decreased somewhat with eccentricity. CONCLUSION: Using HD-OCT, it is possible to acquire retinal data sets containing an unprecedented number of data points. Furthermore, it is possible to use OCT fundus images to evaluate the scan quality and to center the measurement at the fovea. These advantages, together with good automated segmentation, can produce more accurate retinal thickness measurements. Incorporation of the photoreceptor layer in the measurements is anatomically meaningful and may be significant in evaluating various retinal pathologies and visual acuity outcomes.

Three-dimensional spectral-domain optical coherence tomography images of the retina in the presence of epiretinal membranes.

PURPOSE: To study the inner surface of the retina in the presence of epiretinal membranes (ERMs) using a prototype spectral-domain optical coherence tomography (SD-OCT) device. DESIGN: Small case series, performed in the Department of Ophthalmology, Bascom Palmer Eye Institute, Miller School of Medicine, University of Miami, from August 2005 through December 2006. METHOD: An 8-microm axial-resolution SD-OCT instrument was used to scan the eyes of patients diagnosed with ERM. The ERM and the internal limiting membrane (ILM) were segmented separately to evaluate the traction caused by the ERM on the retina. It was then possible to reconstruct the ILM and ERM surfaces in 3-dimensional space and to obtain corresponding retinal thickness maps. RESULTS: SD-OCT B scans showed the points of attachment of the ERM to the ILM. Segmented surface maps of the ERM produced very smooth sheets, whereas those of the ILM presented wrinkles under and around the ERM. CONCLUSIONS: SD-OCT revealed the geometry of retinal traction in eyes with ERM and may be useful in understanding further the pathologic features of these lesions.

Acute-onset endophthalmitis after clear corneal cataract surgery (1996-2005). Clinical features, causative organisms, and visual acuity outcomes.

PURPOSE: To report the clinical features, causative organisms, and visual acuity outcomes associated with endophthalmitis after clear corneal cataract surgery and to compare outcomes with those of the Endophthalmitis Vitrectomy Study (EVS). DESIGN: Retrospective consecutive case series. PARTICIPANTS: The study included 73 eyes of 73 patients, mean age 76 years (range, 48-94 years), with endophthalmitis after clear corneal cataract surgery, including both referred and in-house patients. METHODS: The clinical and microbiology records were reviewed of all patients treated at a single medical center between January 1, 1996, and December 31, 2005, for clinically diagnosed, culture-positive endophthalmitis occurring within 6 weeks of clear corneal cataract surgery. MAIN OUTCOME MEASURES: Presence of hypopyon, mean time to endophthalmitis diagnosis, organisms cultured, and presenting and final visual acuities. RESULTS: The mean time between cataract surgery and diagnosis of endophthalmitis was 13 days (median, 9 days; range, 1-39 days). Visual acuity at the time of diagnosis was <5/200 in 61 of 73 (83.6%) patients, including light perception in 11 of 73 (15.1%). Hypopyon was present in 60 of 73 (82.2%) eyes. The initial treatment included intravitreal vancomycin, ceftazidime, and dexamethasone. A vitreous tap and intravitreal injection was performed in 54 of 73 (74.0%) eyes and pars plana vitrectomy in 19 of 73 (26.0%) eyes. Coagulase-negative Staphylococcus was isolated in 50 of 73 (68.4%) eyes. Other isolates included Staphylococcus aureus in 5/73 (6.8%) and Streptococcus species in 6 of 73 (8.2%). A visual acuity of > or =20/40 was achieved in 36 of 73 patients (49.3%) at final follow-up. CONCLUSIONS: The features and outcomes of endophthalmitis associated with clear corneal cataract surgery are similar to those reported in the EVS, which are associated with scleral incisions, but time to diagnosis was later with clear corneal incisions.

Off-label use of intravitreal bevacizumab (Avastin) for salvage treatment in progressive threshold retinopathy of prematurity.

PURPOSE: To report the short term anatomic response of intravitreal bevacizumab (Avastin, Genentech) as salvage treatment in progressive retinopathy of prematurity (ROP) in a small series of patients. METHODS: The study included five eyes of three patients with progressive ROP despite peripheral laser ablation. Patients received intravitreal injections of bevacizumab (Avastin, Genentech). RetCam (Clarity Medical Systems, Inc., Pleasanton, CA) photography and ultrasonography were used to document effect. RESULTS: Three patients were transferred to the Bascom Palmer Eye Institute/Jackson Memorial Hospital for management of progressive ROP despite laser therapy at an outside facility. RetCam fundus photography and ultrasonography were used to document all cases. After informed consent was obtained from the parents, the patients received off-label intravitreal bevacizumab as salvage treatment. Repeat intravitreal injections of bevacizumab were utilized in several cases. The ROP stabilized allowing laser supplementation. There was varying development of tractional retinal detachments in several of the eyes but the ROP component quieted in all cases. CONCLUSIONS: Off-label use of bevacizumab appears to be useful as a salvage treatment for ROP when laser treatment is precluded. It improves dilation, quiets the disease when visibility is difficult, and temporizes the disease until laser can be supplemented.

Documentation of optic nerve pit with macular schisis-like cavity by spectral domain OCT.

The authors report using spectral domain optical coherence tomography (OCT) to observe a patient with an optic nerve pit and macular schisis-like spaces. An 8-microm axial resolution prototype spectral domain OCT and stereo fundus photography were used to observe the patient. A macular schisis-like cavity was present at baseline and additional cystic changes developed in the nerve fiber layer over a period of 16 months; however, the visual acuity remained stable at 20/20. Spectral domain OCT provides greater detail of the changes in morphology and structure of macular schisis and edema associated with an optic nerve pit.

An optical coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration.

PURPOSE: To evaluate an optical coherence tomography (OCT)-guided, variable-dosing regimen with intravitreal ranibizumab for the treatment of patients with neovascular age-related macular degeneration (AMD). DESIGN: Open-label, prospective, single-center, nonrandomized, investigator-sponsored clinical study. METHODS: In this two-year study, neovascular AMD patients with subfoveal choroidal neovascularization (CNV) (n = 40) and a central retinal thickness of at least 300 microm as measured by OCT were enrolled to receive three consecutive monthly intravitreal injections of ranibizumab (0.5 mg). Thereafter, retreatment with ranibizumab was performed if one of the following changes was observed between visits: a loss of five letters in conjunction with fluid in the macula as detected by OCT, an increase in OCT central retinal thickness of at least 100 microm, new-onset classic CNV, new macular hemorrhage, or persistent macular fluid detected by OCT at least one month after the previous injection of ranibizumab. RESULTS: At month 12, the mean visual acuity improved by 9.3 letters (P < .001) and the mean OCT central retinal thickness decreased by 178 microm (P < .001). Visual acuity improved 15 or more letters in 35% of patients. These visual acuity and OCT outcomes were achieved with an average of 5.6 injections over 12 months. After a fluid-free macula was achieved, the mean injection-free interval was 4.5 months before another reinjection was necessary. CONCLUSION: This OCT-guided, variable-dosing regimen with ranibizumab resulted in visual acuity outcomes similar to the Phase III clinical studies, but required fewer intravitreal injections. OCT appears useful for determining when retreatment with ranibizumab is necessary.

Ranibizumab: Phase III clinical trial results.

Ranibizumab therapy is the first treatment for neovascular AMD to improve vision for most patients. The benefits apply to all angiographic subtypes of neovascular AMD and across all lesion sizes. Although the pivotal phase III trials (MARINA and ANCHOR) used monthly injections of ranibizumab for 2 years, the ongoing PIER, PrONTO, and SAILOR trials are investigating less frequent dosing regimens, and preliminary results from the PrONTO study suggest that fewer injections will most likely result in visual acuity improvements similar to the results from the phase III trials. When comparing the ANCHOR results with the FOCUS results, it also becomes apparent that the combination of ranibizumab with PDT does not necessarily result in better visual acuity outcomes, and the use of PDT may even reduce the visual acuity benefits achieved with ranibizumab alone (see Figs. 1-3). It seems unlikely that combination therapy provides any significant advantage over ranibizumab alone unless the combination of PDT and ranibizumab can decrease the need for frequent retreatment. The results from the PrONTO Study already suggest that less frequent treatment with ranibizumab is possible by using a variable dosing regimen with OCT. Ranibizumab also seems to be safe, with the 2-year MARINA data showing no increase in the incidence of systemic adverse events that could be associated with anti-VEGF therapy, such as myocardial infarction and stroke. There was a hint of a safety concern, however, in the pooled 1-year safety results from the MARINA and ANCHOR trials. Although the combined rate of myocardial infarction and stroke during the first year of the ANCHOR and MARINA trials was similar in the control and the 0.3-mg ranibizumab arms (1.3% and 1.6% respectively), these adverse events were slightly higher in the 0.5-mg ranibizumab arm (2.9%). These differences are not statistically significant, however, and probably do not represent a dose-dependent increase in risk because the 2-year results from the MARINA trial with the same monthly injection regimen showed no increased risk of thromboembolic events. In December 2005, Genentech submitted a Biologics License Application to the FDA for the use of ranibizumab in the treatment of neovascular wet AMD based on 1-year clinical efficacy and safety data from the two pivotal phase III trials, ANCHOR and MARINA, and the phase I-II FOCUS trial. Genentech has been granted a 6-month Priority Review from the FDA with a decision anticipated 6 months from the December submission date or by the end of June 2006 [29]. By the summer of 2006, this revolutionary therapy should be available for the treatment of neovascular AMD. At that time, the major dilemma facing most retina specialists will be whether to use intravitreal ranibizumab or intravitreal bevacizumab, the low cost alternative, for the treatment of neovascular AMD.

Short-term safety and efficacy of intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration.

PURPOSE: To evaluate the safety and efficacy of intravitreal bevacizumab (Avastin, Genentech Inc.) for the treatment of neovascular age-related macular degeneration (ARMD). METHODS: A retrospective review was performed on consented patients with neovascular ARMD receiving intravitreal bevacizumab therapy. All patients received intravitreal bevacizumab at baseline with additional monthly injections given at the discretion of the treating physician. At each visit, a routine Snellen visual acuity assessment was performed followed by an ophthalmic examination and optical coherence tomography (OCT) imaging. RESULTS: Fifty-three eyes of 50 patients received an intravitreal bevacizumab injection between May and August 2005. Including the month 3 visit, the average number of injections was 2.3 out of a maximum of 4 injections. No serious drug-related ocular or systemic adverse events were identified. Improvements in visual acuity and central retinal thickness measurements were evident by week 1 and continued through month 3. At month 3, the mean visual acuity improved from 20/160 to 20/125 (P < 0.001) and the mean central retinal thickness decreased by 99.6 microm (P < 0.001). CONCLUSION: Off-label intravitreal bevacizumab therapy for neovascular ARMD was well tolerated over 3 months with improvements in visual acuity and OCT central retinal thickness measurements. While the long-term safety and efficacy of intravitreal bevacizumab remain unknown, these short-term results suggest that intravitreal bevacizumab may be the most cost effective therapy for the treatment of neovascular ARMD.