International Classification System for Ocular Complications of Anti-Vascular Endothelial Growth Factor Agents in Clinical Trials.

OBJECTIVE: Complications associated with intravitreal anti-vascular endothelial growth factor (VEGF) therapies are inconsistently reported in the literature, thus limiting an accurate evaluation and comparison of safety between studies. This study aimed to develop a standardized classification system for anti-VEGF ocular complications using the Delphi consensus process. DESIGN: Systematic review and Delphi consensus process. PARTICIPANTS: 25 international retinal specialists participated in the Delphi consensus survey. METHODS: A systematic literature search was conducted to identify complications of intravitreal anti-VEGF agent administration based on randomized controlled trials (RCTs) of anti-VEGF therapy. A comprehensive list of complications was derived from these studies, and this list was subjected to iterative Delphi consensus surveys involving international retinal specialists that voted on inclusion, exclusion, rephrasing, and addition of complications. As well, surveys determined specifiers for the selected complications. This iterative process helped refine the final classification system. MAIN OUTCOME MEASURES: The proportion of retinal specialists who choose to include or exclude complications associated with anti-VEGF administration. RESULTS: After screening 18,229 articles, 130 complications were initially categorized from 145 included RCTs. Participant consensus via the Delphi method resulted in the inclusion of 91 (70%) complications after three rounds. After incorporating further modifications made based on participant suggestions, such as rewording certain phrases and combining similar terms, 24 redundant complications were removed, leaving a total of 67 (52%) complications in the final list. A total of 14 (11%) complications met exclusion thresholds and were eliminated by participants across both rounds. All other remaining complications not meeting inclusion or exclusion thresholds were also excluded from the final classification system after the Delphi process terminated. In addition, 47 out of 75 (63%) proposed complication specifiers were included based on participant agreement. CONCLUSION: Using the Delphi consensus process, a comprehensive, standardized classification system consisting of 67 ocular complications and 47 unique specifiers was established for intravitreal anti-VEGF agents in clinical trials. The adoption of this system in future trials could improve consistency and quality of adverse event reporting, potentially facilitating more accurate risk-benefit analyses.

Dopamine receptor signaling regulates fibrotic activation of retinal pigmented epithelial cells.

Retinal pigmented epithelial (RPE) cells play an important role in retinal fibrotic diseases such as proliferative vitreoretinopathy (PVR). The purpose of this study was to elucidate the involvement of dopamine receptor signaling in regulating the fibrotic activation of RPE cells. Dopamine receptor expression, the effect of dopamine on fibrotic activity, and dopamine production were measured in the human RPE cell line ARPE-19. The fibrotic activation of RPE cells was evaluated in response to treatments with selective dopamine receptor agonists and antagonists by measuring gene expression, migration, proliferation, and fibronectin deposition. DRD2 and DRD5 are the dominant dopaminergic receptors expressed in ARPE-19 cells and TGF-ß stimulation enhances the autocrine release of dopamine, which we show further exasperates fibrotic activation. Finally, treatment with D2 dopamine receptor antagonists or D5 dopamine receptor agonists inhibits profibrotic gene expression, migration, proliferation, and fibronectin deposition and thus may serve as effective mechanisms for treating retinal fibrosis including PVR.

The 12- and 24-Month Effects of Intravitreal Ranibizumab, Aflibercept, and Bevacizumab on Intraocular Pressure: A Network Meta-Analysis.

TOPIC: To investigate the effect of anti-vascular endothelial growth factor (VEGF) therapy on intraocular pressure (IOP) 12 and 24 months after initiation. CLINICAL RELEVANCE: It is unclear whether serial anti-VEGF injections result in sustained IOP increases. METHODS: Randomized controlled trials (RCTs) comparing anti-VEGF agents with each other or with controls for the treatment of neovascular age-related macular degeneration, retinal vein occlusions, or diabetic macular edema were included. Pairwise meta-analysis and Bayesian network meta-analysis examined the proportion of patients whose IOP (1) increased 5 mmHg or more from baseline on consecutive visits, (2) increased 10 mmHg or more from baseline at any visit, (3) was 21 mmHg or more on consecutive visits, (4) was 25 mmHg or more at any visit, (5) was 30 mmHg or more at any visit, (6) prompted initiation of IOP-lowering medications, or (7) increased as per the clinicians' discretion. Grading of Recommendations Assessments, Development, and Evaluations methodology informed the certainty of evidence. RESULTS: Twenty-six RCTs of 12 522 eyes were included. Aflibercept, bevacizumab, ranibizumab (0.3 mg and 0.5 mg), and noninjection controls were analyzed. Eighty-three of 84 network estimates for comparisons between anti-VEGF agents demonstrated no statistically significant difference (low to moderate certainty of evidence). Ranibizumab 0.5 mg showed higher rates than bevacizumab of IOP measurements of 30 mmHg or more at 12 months (low certainty of evidence). Fifty-three of 56 network estimates for comparisons between anti-VEGF agents and controls demonstrated no statistically significant difference (low to moderate certainty of evidence). Ranibizumab 0.5 mg showed higher rates of consecutive IOP increases of 5 mmHg or more at 24 months (low certainty of evidence) and higher rates of IOP increases as per the clinicians' discretion at 12 and 24 months (low and very low certainty of evidence, respectively). The 95% credible intervals in comparisons without statistically significant effects did not rule out important clinical effects. The certainty of evidence in these comparisons is limited by imprecision. CONCLUSION: This network meta-analysis does not show any clear difference in IOP increases 12 and 24 months after treatment initiation between anti-VEGF agents and controls. Imprecision precludes definitive conclusions.

EFFECT OF PHYSICIAN FACE MASK USE ON POSTINJECTION ENDOPHTHALMITIS.

PURPOSE: To examine the impact of physician face mask use on the rates and outcomes of postinjection endophthalmitis. METHODS: A multicenter retrospective, comparative cohort study comparing endophthalmitis rate and visual acuity of eyes that developed endophthalmitis after antivascular endothelial growth factor injections at Mayo Clinic Rochester (MCR) and at Mayo Clinic Health System sites depending on physician masking. RESULTS: A total of 164,824 injections were performed at MCR and Mayo Clinic Health System sites. Of these, 66,098 injections were in the no mask group and 98,726 injections were in the mask group. Overall, there were no differences in the rates of infectious endophthalmitis in the no mask versus mask cohorts (overall: no mask: 20 cases [0.0303%] vs. mask: 41 cases (0.0415%); P = 0.24; infectious: no mask: 12 cases [0.018%] versus mask: 13 cases [0.0132%]; P = 0.42). At MCR alone, there was a significant reduction in infectious endophthalmitis between the no mask versus mask groups (no mask: 9 cases [0.0297%] versus mask: 2 cases [0.003%]; P < 0.001). Only 2 cases of infectious endophthalmitis occurred at MCR after the face mask policy was implemented (1 in 30,000 injections). At presentation and at 6 months, the average visual acuity was similar for patients who developed endophthalmitis between the no mask versus mask groups. CONCLUSION: Physician face mask use did not affect the rate or outcome of postinjection endophthalmitis. However, there was a significant reduction at MCR after masking along with other quality improvement measures, including performance of injections in a dedicated procedure room and preparation of patients by nurses, that led to a low rate of endophthalmitis.

Supplemental Scleral Buckle for the Management of Rhegmatogenous Retinal Detachment by Pars Plana Vitrectomy: A Meta-Analysis of Randomized Controlled Trials.

OBJECTIVES: The present review aimed to synthesize evidence from randomized controlled trials (RCTs) that compared outcomes of pars plana vitrectomy (PPV) with and without a supplementary scleral buckle (SB) for management of rhegmatogenous retinal detachment (RRD). METHODS: The authors searched MEDLINE, Embase, and CENTRAL to identify RCTs in English that compared PPV with and without supplemental SB. Risk of bias was assessed according to the Cochrane Risk of Bias 2 tool. We present risk ratios (RRs), mean differences (MDs), and 95% confidence intervals (CIs) estimated using random-effects meta-analyses. RESULTS: We identified 6 RCTs involving 705 eyes. Primary reattachment (6 studies, 345 eyes PPV, 324 eyes PPV + SB; RR 0.99, 95% CI 0.93-1.06, I2 = 0%, p = 0.78) and final anatomic success rates (4 studies, 272 eyes PPV, 267 eyes PPV + SB; RR 1.00, 95% CI 0.98-1.02, I2 = 0%, p = 0.89) were similar between the 2 groups. Postoperative visual acuity improvement (5 studies, 244 eyes PPV, 222 eyes PPV + SB; MD 6.09 letters, 95% CI -0.47-12.64, I2 = 69%, p = 0.07) and frequency of adverse events (6 studies, 1,294 observations PPV, 1,221 observations PPV + SB; RR 0.76, 95% CI 0.57-1.01, I2 = 25%, p = 0.06) likewise did not differ significantly between the treatment groups. CONCLUSION: Low-certainty evidence from RCTs did not demonstrate a benefit in placement of a supplemental SB during vitrectomy for management of RRD in the current analysis. Additional high-quality trials are needed to provide more precise estimates of the effect.

Systemic Corticosteroid Use after Central Serous Chorioretinopathy Diagnosis.

PURPOSE: To analyze the frequency of systemic corticosteroid prescriptions before and after central serous chorioretinopathy (CSC) diagnosis. DESIGN: Retrospective claims-based analysis. PARTICIPANTS: A nationally representative sample of commercial insurance beneficiaries who received care between 2007 and 2015. METHODS: We limited the study population to beneficiaries with incident CSC diagnosed by an eye care provider, excluding those with other major ophthalmologic comorbidities. We developed a non-CSC comparison cohort matched to CSC patients by age, sex, general health (Charlson Comorbidity Index), and geographic region. We compared systemic corticosteroid prescriptions before and after CSC diagnosis and by diagnosing provider (optometrist vs. ophthalmologist) and evaluated likelihood of steroids treatment among CSC versus matched control patients using logistic and Cox proportional hazard regression models. MAIN OUTCOME MEASURES: Systemic corticosteroid prescription frequency among CSC patients within 12 months pre-diagnosis and at 6, 12, and 24 months post-diagnosis, median time to steroid initiation and discontinuation, and odds of receiving steroids post-diagnosis among CSC and control patients. RESULTS: We identified 3418 CSC patients. Nearly 39% (n = 1326) were prescribed systemic steroids at some point during the analysis period, versus 23% of controls (4033 of 17 178 patients). Over 12% of CSC patients (n = 430) within 1 year pre-diagnosis, and nearly 12% (n = 404) within 1 year post-diagnosis. Most patients who received steroids after diagnosis were steroid naive (n = 231). Among those receiving steroids, CSC patients demonstrated longer median time to first post-diagnosis steroid prescription (1.82 years vs. 0.50 years for non-CSC patients) and longer time to last steroid prescription (1.62 years vs. 0.35 years for non-CSC patients). Although CSC patients were significantly less likely to receive steroids within 6 months post-diagnosis compared with non-CSC patients (odds ratio, 0.72; 95% confidence interval, 0.59-0.89), they were significantly more likely to receive steroids by 2 years post-diagnosis. Prescribing patterns were similar for patients diagnosed by an ophthalmologist versus optometrist. CONCLUSIONS: Despite evidence showing that steroids contribute to CSC development, many patients continue to be prescribed systemic corticosteroids after CSC diagnosis. Our results suggest a need for greater communication and collaboration among providers to ensure that clinical practice reflects evidence-based recommendations.

TEN-YEAR FOLLOW-UP OF PATIENTS WITH EXUDATIVE AGE-RELATED MACULAR DEGENERATION TREATED WITH INTRAVITREAL ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR INJECTIONS.

PURPOSE: To identify the visual acuity outcomes of patients with age-related macular degeneration treated with intravitreal anti-vascular endothelial growth factor injections over a 10-year period. METHODS: This was a retrospective, cohort study of eyes with exudative age-related macular degeneration that received ≥2 intravitreal anti-vascular endothelial growth factor injections and had at least 10 years of follow-up after the initiation of treatment. Snellen visual acuity was recorded at baseline and then annually until the last year of follow-up. Optical coherence tomography data were collected at the time of treatment initiation and at the last examination visit. A subanalysis was performed on patients who continued to receive anti-vascular endothelial growth factor therapy using a modified treat and extend protocol versus those who discontinued treatment for longer than 1 year. RESULTS: One hundred thirty eyes of 115 patients met the inclusion criteria. The mean follow-up after treatment initiation was 11.1 ± 0.7 years. Eyes received an average of 45.1 ± 32.3 intravitreal injections in total and a mean of 5 to 7 injections per year. The baseline mean logMAR visual acuity was 0.61 ± 0.5 (Snellen acuity 20/81), and the final mean logMAR visual acuity was 0.88 ± 0.7 (20/152, P value = <0.0001). There were 40 eyes that received at least one injection every year. These eyes did not have a significant change in visual acuity between the baseline and final examinations 0.47 ± 0.4 (20/59 vs. 0.58 ± 0.5 [20/76, P = 0.28]), whereas the eyes that did not receive at least one injection every year saw a significant decline in visual acuity 0.67 ± 0.5 (20/94 vs. 1.01 ± 0.7 [20/205, P < 0.0001]). CONCLUSION: Eyes with exudative age-related macular degeneration that received intravitreal injections every year had stable visual acuity over a 10-year period. Continuous intravitreal anti-vascular endothelial growth factor therapy may stabilize visual acuity for 10 years and potentially longer.

INCREASED INCIDENCE OF CUTANEOUS KERATINOCYTIC AND MELANOCYTIC MALIGNANCIES IN PATIENTS WITH AGE-RELATED MACULAR DEGENERATION.

PURPOSE: The relationship between age-related macular degeneration (AMD) and malignancy, especially cutaneous malignancies, is not well studied. We investigated a possible association between AMD and cutaneous malignancies. METHODS: A retrospective, consecutive review of all patients who had received at least 1 intravitreal injection for wet AMD between January 1, 2004, and December 31, 2013, was conducted using the Rochester Epidemiology Project in Olmsted County, Minnesota. Age- and sex-matched control groups included 473 pre-anti-vascular endothelial growth factor era wet AMD patients, 504 concurrent time dry AMD patients, and 504 patients with no AMD. The rates of AMD and overall malignancy, cutaneous malignancies, and specific types of cutaneous malignancies were compared between groups of patients. RESULTS: Patients with wet AMD incurred an increased rate of overall malignancies compared to patients with dry AMD {52.8% wet AMD (confidence interval [CI]: 48.3-57.2) vs. 43.7% dry AMD (CI: 39.3-48.1); P= 0.003} or those without AMD (52.8% wet AMD [CI: 48.3-57.2] vs. 35.3% no AMD [CI: 31.1-39.7]; P = <0.001). Patients with dry AMD also had higher rates of malignancy than those without AMD (43.7% dry AMD [CI: 39.3-48.1] vs. 35.3% no AMD [CI: 31.1-39.7]; P = 0.007). Rate of cutaneous malignancies was increased in patients with wet AMD compared to patients with dry AMD (24.4% wet AMD [CI: 20.7-28.4] vs. 14.6% dry AMD [CI: 11.5-17.9]; P = <0.001) and those with no AMD (24.4% wet AMD [CI: 20.7-28.4] vs. 9.7% no AMD [CI: 7.3-12.7]; P = <0.001). CONCLUSION AND RELEVANCE: To the best of our knowledge, this is the first report to establish an association between AMD and cutaneous malignancies, supporting a possible discussion of the association when a patient presents with one of the two conditions.

Safety and Efficacy of Anti-Vascular Endothelial Growth Factor Therapies for Neovascular Age-Related Macular Degeneration: A Report by the American Academy of Ophthalmology.

PURPOSE: To review the evidence on the safety and efficacy of anti-vascular endothelial growth factor (VEGF) therapies for the treatment of neovascular age-related macular degeneration (AMD). METHODS: A literature search of the PubMed and Cochrane Library databases was last conducted in February 2017; there were no date restrictions, and the search was limited to studies published in English. The combined searches yielded 191 citations, 28 of which were selected because they were clinical trials and were deemed clinically relevant for the Ophthalmic Technology Assessment Committee Retina/Vitreous Panel to review in full. The panel methodologist then assigned a level of evidence rating to each study. RESULTS: Sixteen of the 28 citations provided level I evidence supporting the use of anti-VEGF agents for neovascular AMD, including intravitreal ranibizumab, aflibercept, and bevacizumab. Eight studies reviewed provided level II evidence, and 4 studies provided level III evidence, but only the level I studies are included in this assessment. There are long-term follow-up data on the efficacy of ranibizumab and bevacizumab (≥5 years), but these data are subject to the bias of incomplete follow-up. CONCLUSIONS: Review of the literature indicates that intravitreal injection of anti-VEGF therapy is safe and effective for neovascular AMD over 2 years, the period for which data are available. Further research is needed to evaluate the long-term safety and comparative efficacy of these agents.

Therapies for Macular Edema Associated with Branch Retinal Vein Occlusion: A Report by the American Academy of Ophthalmology.

PURPOSE: To evaluate the available evidence on the ocular safety and efficacy of current therapeutic alternatives for the management of macular edema (ME) secondary to branch retinal vein occlusion (BRVO). METHODS: Literature searches were last conducted on January 31, 2017, in PubMed with no date restrictions and limited to articles published in English, and in the Cochrane Database without language limitations. The searches yielded 321 citations, of which 109 were reviewed in full text and 27 were deemed appropriate for inclusion in this assessment. The panel methodologist assigned ratings to the selected studies according to the level of evidence. RESULTS: Level I evidence was identified in 10 articles that addressed anti-vascular endothelial growth factor (VEGF) pharmacotherapies for ME, including intravitreal bevacizumab (5), aflibercept (2), and ranibizumab (4). Level I evidence was identified in 6 studies that examined intravitreal corticosteroids, including triamcinolone (4) and the dexamethasone implant (2). Level I evidence also was available for the role of macular grid laser photocoagulation (7) and scatter peripheral laser surgery (1). The inclusion of level II and level III studies was limited given the preponderance of level I studies. The number of studies on combination therapy is limited. CONCLUSIONS: Current level I evidence suggests that intravitreal pharmacotherapy with anti-VEGF agents is effective and safe for ME secondary to BRVO. Prolonged delay in treatment is associated with less improvement in visual acuity (VA). Level I evidence also indicates that intravitreal corticosteroids are effective and safe for the management of ME associated with BRVO; however, corticosteroids are associated with increased potential ocular side effects (e.g., elevated intraocular pressure, cataracts). Laser photocoagulation remains a safe and effective therapy, but VA results lag behind the results for anti-VEGF therapies.

Diagnosis and Treatment of Acute Retinal Necrosis: A Report by the American Academy of Ophthalmology.

PURPOSE: To evaluate the available evidence in peer-reviewed publications about the diagnosis and treatment of acute retinal necrosis (ARN). METHODS: Literature searches of the PubMed and Cochrane Library databases were last conducted on July 27, 2016. The searches identified 216 unique citations, and 49 articles of possible clinical relevance were reviewed in full text. Of these 49 articles, 27 were deemed sufficiently relevant or of interest, and they were rated according to strength of evidence. An additional 6 articles were identified from the reference lists of these articles and included. All 33 studies were retrospective. RESULTS: Polymerase chain reaction (PCR) testing of aqueous or vitreous humor was positive for herpes simplex virus (HSV) or varicella zoster virus (VZV) in 79% to 100% of cases of suspected ARN. Aqueous and vitreous specimens are both sensitive and specific. There is level II and III evidence supporting the use of intravenous and oral antiviral therapy for the treatment of ARN. Data suggest that equivalent plasma drug levels of acyclovir can be achieved after administration of oral valacyclovir or intravenous acyclovir. There is level II and III evidence suggesting that the combination of intravitreal foscarnet and systemic antiviral therapy may have greater therapeutic efficacy than systemic therapy alone. The effectiveness of prophylactic laser or early pars plana vitrectomy (PPV) in preventing retinal detachment (RD) remains unclear. CONCLUSIONS: Polymerase chain reaction testing of ocular fluid is useful in supporting a clinical diagnosis of ARN, but treatment should not be delayed while awaiting PCR results. Initial oral or intravenous antiviral therapy is effective in treating ARN. The adjunctive use of intravitreal foscarnet may be more effective than systemic therapy alone. The role of prophylactic laser retinopexy or early PPV is unknown at this time.

OUTCOMES OF AN INTRAVITREAL INJECTION CLINIC.

PURPOSE: To examine the safety outcomes of an intravitreal injection-only clinic where patients needing long-term anti-vascular endothelial growth factor therapy are treated with injections at a predetermined interval for a set number of injections without an accompanying clinic visit. METHODS: This is a retrospective chart review of all patients with exudative macular degeneration treated in an intravitreal injection clinic over a 4-year period. Data on the outcome measures of interest were gathered from electronic medical records. RESULTS: There were 556 patients who received 4,386 injections in the injection-only clinic in a total of 1,524 injection cycles. One hundred six cycles were interrupted. The most common causes for interruption were decreased vision in the injected eye (32), decreased vision in the fellow eye (23), flashing lights (6), pain (5), and irritation in the noninjected eye (2). Of patients who had interruption of the cycle, 32 had a new diagnosis (6 corneal abrasions, 6 exudative age-related macular degeneration in fellow eye). There were six instances of conversion to exudative age-related macular degeneration found in the other eye at a routine follow-up visit following the injection clinic. CONCLUSION: An injection-only clinic may provide a reasonable approach to streamline retina practices to ensure that patients receive timely injections.

Systemic safety of intravitreal anti-vascular endothelial growth factor agents in age-related macular degeneration.

PURPOSE OF REVIEW: The purpose of review is to summarize the literature addressing nonocular adverse events in patients with neovascular age-related macular degeneration treated with intravitreal vascular endothelial growth factor (VEGF) inhibitors and to present possible mechanisms of effect. RECENT FINDINGS: The incidence of overall nonocular serious adverse events varied from 0 to 39.3% and nonocular adverse events ranged from 0 to 86.9%. Few studies have reported a significant association between use of intravitreal anti-VEGF agents and overall incidence of adverse events, stroke, myocardial infarction, nonocular hemorrhage and death, with overall greater concern in patients treated with bevacizumab. Additionally, history of stroke or other arterial thromboembolic event may be a risk factor for future stroke in patients treated with intravitreal anti-VEGF agents. Theories explaining the mechanisms of increased risk of nonocular adverse events secondary to anti-VEGF agent use surround the necessity of VEGF for the normal functioning of the endothelium and the damage incurred with use of anti-VEGF agents. SUMMARY: Current data are insufficient to definitively conclude that intravitreal anti-VEGF agents are safe, although there is a trend toward an overall favorable systemic safety profile. Caution should be exerted in patients with a history of cardiovascular disease, as these patients may be at greater risk for nonocular serious adverse events.

EVALUATION OF MULTIPLE DEXAMETHASONE INTRAVITREAL IMPLANTS IN PATIENTS WITH MACULAR EDEMA ASSOCIATED WITH RETINAL VEIN OCCLUSION.

BACKGROUND: Limited data have evaluated multiple injections of the dexamethasone 700 µg implant (DEX) (Ozurdex; Allergan, Inc.) for cystoid macular edema (CME) secondary to retinal vein occlusion (RVO) over an extended regimen. METHODS: This retrospective study evaluated patients treated with DEX for CME associated with RVO. Each patient had ophthalmologic evaluation, optical coherence tomography (OCT), and 4 weeks to 6 weeks follow-up intervals. Retreatment criterion was fluid on OCT. Outcome measures included best-corrected visual acuity, intraocular pressure (IOP), central macular thickness on OCT, fluid resolution on OCT, and required treatment for elevated IOP and cataract. RESULTS: Thirty-one patients had 82 DEX injections, with 19 patients having ≥2, 12 having ≥3, 10 having ≥4, 6 having ≥5, and 4 having ≥6 DEX injections. All patients were followed at least 12 weeks and had a mean follow-up period of 344.94 days. Fourteen patients (45%) developed ocular hypertension (≥22 mmHg), and 40% of phakic patients required cataract surgery. Mean interval of OCT fluid resolution was 52 days (range, 28-245; SD, ±8), and mean retreatment interval was 119 days (range, 42-309; SD, ±9). No patients required glaucoma surgery or developed endophthalmitis. CONCLUSION: This study suggests that repeated, as needed, DEX injections for CME associated with RVO may be performed. Patients should be monitored and treated for ocular hypertension and cataract progression.

Topical Nonsteroidal Anti-inflammatory Drugs and Cataract Surgery: A Report by the American Academy of Ophthalmology.

OBJECTIVE: To review the available evidence on the effectiveness of prophylactic topical nonsteroidal anti-inflammatory drugs (NSAIDs) in preventing vision loss resulting from cystoid macular edema (CME) after cataract surgery. METHODS: Literature searches of the PubMed and the Cochrane Library databases were last conducted on January 21, 2015, with no date restrictions. The searches retrieved 149 unique citations. The first author reviewed the abstracts of these articles and selected 27 articles of possible clinical relevance for full-text review. Of these 27 articles, 12 were deemed relevant to analyze in full. Two additional articles were identified from the reference list of the selected articles, and another article was identified from a national meeting. The panel methodologist assigned ratings of level of evidence to each of the selected citations. RESULTS: Nonsteroidal anti-inflammatory drug therapy was effective in reducing CME detected by angiography or optical coherence tomography (OCT) and may increase the speed of visual recovery after surgery when compared directly with placebo or topical corticosteroid formulations with limited intraocular penetration. However, the use of NSAIDs did not alter long-term (≥3 months) visual outcomes. Furthermore, there was no evidence that the benefits observed with NSAID therapy could not be obtained similarly with equivalent dosing of a corticosteroid. The reported impression that there is a pharmacologic drug synergy from the use of both an NSAID and a corticosteroid is not supported by the literature. There is no uniform method of reporting CME in the literature, which prevents accurate assessment of its incidence and response to anti-inflammatory therapies. CONCLUSIONS: Cystoid macular edema after cataract surgery has a tendency to resolve spontaneously. There is a lack of level I evidence that supports the long-term benefit of NSAID therapy to prevent vision loss from CME at 3 months or more after cataract surgery. Although dosing of NSAIDs before surgery may hasten the speed of visual recovery in the first several weeks after cataract surgery, there is no evidence that this practice affects long-term visual outcomes. Standardized reporting of CME based on OCT may allow for more uniform quantitation of its incidence and more reliable assessment of treatment outcomes.

Therapies for macular edema associated with central retinal vein occlusion: a report by the American Academy of Ophthalmology.

PURPOSE: To review the available evidence regarding the safety and efficacy of therapies for the treatment of macular edema (ME) associated with central retinal vein occlusion (CRVO). METHODS: A literature search of the PubMed database was last conducted in March 2014 with no date restrictions but limited to articles published in English. A literature search of the Cochrane Library was also conducted in March 2014 with no date restrictions and without a language limitation. The combined searches yielded 108 citations, of which 20 were deemed clinically relevant for the Ophthalmic Technology Assessment Committee Retina/Vitreous panel to review in full text. Three additional studies were also identified for panel review. The level of evidence of these selected studies was reviewed by the panel methodologist. RESULTS: There were 7 citations representing 4 clinical trials that provided level I evidence supporting the use of anti-vascular endothelial growth factor (VEGF) pharmacotherapies for ME associated with CRVO, including intravitreal ranibizumab (2), aflibercept (3), and bevacizumab (2). There were 3 citations representing 2 studies with level I evidence for intravitreal corticosteroid injection with dexamethasone intravitreal implant (2 citations) or triamcinolone (1 citation), although cataract and glaucoma were observed in these studies. Level I evidence is available on the limited benefit of macular grid-pattern laser photocoagulation (1 citation). Eight other citations reviewed were rated as level II, and 4 citations were rated as level III. Long-term efficacy results (≥2 years of follow-up) are limited to intravitreal ranibizumab at this time, and few studies have evaluated combination therapy with anti-VEGF and corticosteroid versus monotherapy of either class of drug. CONCLUSIONS: Level I evidence indicates that intravitreal anti-VEGF pharmacotherapy is safe and effective over 2 years for ME associated with CRVO and that delay in treatment is associated with worse visual outcomes. In addition, level I evidence demonstrates short-term efficacy of intravitreal corticosteroid but also an association with a higher frequency of adverse events.

SUSTAINED ELEVATION OF INTRAOCULAR PRESSURE AFTER INTRAVITREAL ANTI-VEGF AGENTS: What Is the Evidence?

PURPOSE: To summarize the literature addressing sustained and delayed elevation of intraocular pressure (IOP) in patients with neovascular age-related macular degeneration being treated with intravitreal vascular endothelial growth factor (VEGF) inhibitors and to present possible mechanisms of effect. METHODS: Analysis of current literature evaluating sustained and delayed elevation of IOP in patients receiving intravitreal anti-VEGF therapy for neovascular age-related macular degeneration. RESULTS: Studies have demonstrated that patients undergoing treatment with intravitreal anti-VEGF agents may experience sustained and delayed elevation of IOP. The incidence of sustained elevation of IOP in patients with neovascular age-related macular degeneration varied from 3.45% to 11.6%, and few patients required surgical management to control IOP. Possible risk factors associated with sustained and delayed elevation of IOP include, but are not limited to, history of glaucoma, phakia, history of glucocorticoid use, and/or extended treatment duration. There are multiple theories explaining the pathogenesis of sustained elevation of IOP, including microparticle obstruction of the trabecular meshwork, intraocular inflammation, and transient elevation of IOP. CONCLUSION: Sustained and delayed elevation of IOP in patients undergoing treatment of neovascular age-related macular degeneration with intravitreal anti-VEGF agents is likely a multifactorial process. Further studies to prospectively investigate sustained elevation of IOP in large, randomized, controlled trials might lead to a better understanding of the long-term adverse events associated with intravitreal anti-VEGF therapy.

Pharmacogenomics of response to anti-VEGF therapy in exudative age-related macular degeneration.

PURPOSE: To determine whether there is an association between response to intravitreal anti-vascular endothelial growth factor agents and genotype in patients with neovascular age-related macular degeneration. METHODS: Analysis of the current literature evaluating pharmacogenetics of treatment response in patients with neovascular age-related macular degeneration. RESULTS: Studies have demonstrated associations between various genotypes and response to intravitreal anti-vascular endothelial growth factor agents. Lower-risk genotypes of the CFH, ARMS2, HTRA1, and VEGF-A genes may be associated with improved visual outcomes. Additionally, frequency of injections may be associated with certain genotypes. CONCLUSION: Genetic background may influence an individual's response to treatment of neovascular age-related macular degeneration. Further studies to investigate biologic pathways of neovascular age-related macular degeneration and gene products that are directly involved might lead to better understanding of contribution of various genes to treatment response.

Intraocular pressure in eyes receiving monthly ranibizumab in 2 pivotal age-related macular degeneration clinical trials.

PURPOSE: To characterize preinjection intraocular pressure (IOP) in eyes receiving monthly ranibizumab versus sham or verteporfin photodynamic therapy (PDT) for age-related macular degeneration (AMD). DESIGN: Post hoc analysis of IOP data from 2 phase 3 clinical trials, the Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD (MARINA) and the Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD (ANCHOR) trial. PARTICIPANTS: All safety-evaluable patients who received 1 or more injections of sham or PDT or of ranibizumab and had 1 or more postbaseline IOP measurements recorded for the study eye. METHODS: Preinjection IOP measurements for study eyes (n = 1125) and fellow eyes in MARINA and ANCHOR at baseline and at each monthly visit through month 24 were analyzed. MAIN OUTCOME MEASURES: End points evaluated were maximum preinjection IOP during the 24-month treatment period; any occurrence of absolute preinjection IOP of 21 mmHg or more, 25 mmHg or more, or 30 mmHg or more; any occurrence of IOP increase of 6 mmHg or more, 8 mmHg or more, or 10 mmHg or more from baseline; any combination of IOP increase of 6 mmHg or more or 8 mmHg or more from baseline with concurrent absolute preinjection IOP of 21 mmHg or more or 25 mmHg or more; glaucoma-related adverse events; new glaucoma medications used for 45 days or more; and glaucoma filtration or laser surgeries. RESULTS: Across treatment groups, 60.1% to 70.9% of study eyes had a maximum preinjection IOP of less than 21 mmHg. Comparing ranibizumab 0.5 mg versus sham or PTD treatment, respectively: 39.9% versus 29.1% and 10.9% versus 5.1% had maximum preinjection IOPs of 21 mmHg or more or 25 mmHg or more, respectively; 44.1% versus 29.9% and 24.2% versus 13.6% had IOP increases from baseline of 6 mmHg or more or 8 mmHg or more, respectively; 26.1% versus 13.6% and 16.8% versus 9.0% had 1 or more IOP increase from baseline of 6 mmHg or more or 8 mmHg or more, respectively, with a concurrent IOP of 21 mmHg or more; 9.6% versus 3.7% and 7.5% versus 2.4% had 1 or more IOP increase from baseline of 6 mmHg or more or 8 mmHg or more, respectively, with a concurrent IOP of 25 mmHg or more. No differences were observed in fellow eyes. CONCLUSIONS: Most ranibizumab-treated eyes did not experience sustained preinjection IOP of 21 mmHg or more (>2 consecutive visits) over 24 months. When evaluating the combined IOP end point, more ranibizumab-treated eyes had 1 or more IOP increase from baseline of 6 mmHg or more or 8 mmHg or more, with concurrent highest IOPs of 21 mmHg or more and 25 mmHg or more versus sham or PDT. Intraocular pressure should be monitored in eyes receiving ranibizumab.

Intravitreal injection technique and monitoring: updated guidelines of an expert panel.

PURPOSE: To review evidence and provide updated guidelines on intravitreal (IVT) injection technique and monitoring. METHODS: A review of the published literature on IVT injection from 2004 to 2014 formed the basis for round table deliberations by an expert panel of ophthalmologists. RESULTS: The dramatic increase in the number of IVT injections has been accompanied by a comparable increase in evidence surrounding IVT practice patterns and techniques. The expert panel identified a number of areas that have evolved since publication of the original IVT injection guidelines in 2004, the most notable of which were a lack of evidence to support the routine use of pre-, peri-, and postinjection antibiotics to reduce the risk of endophthalmitis, and the role of aerosolized droplets containing oral contaminants from the patient and/or providers as a potential source of infection. The panel emphasized the continued importance of applying povidone-iodine to and avoiding eyelid contact with the intended injection site and needle. CONCLUSION: Updated guidelines on IVT injection technique and monitoring are proposed based on a review of published literature and expert panel deliberations.