Volume 9, Number 2
February 2013


WELCOME to Review of Ophthalmology's Retina Online e-newsletter. Each month, Medical Editor Philip Rosenfeld, MD, PhD, and our editors provide you with this timely and easily accessible report to keep you up to date on important information affecting the care of patients with vitreoretinal disease.

FDA Accepts IND for Optina to Treat DME
The FDA has accepted Ampio Pharmaceuticals Inc.'s IND for Optina for the treatment of diabetic macular edema (DME)...

New Line of Vitreoretinal Devices and Instruments From FCI Ophthalmics
FCI Ophthalmics has introduced a new line of devices and instruments designed to provide retina surgeons with high-performance products for vitreoretinal procedures...

And More...

Risk of AMD in Aspirin Users

Researchers conducted a prospective analysis of data from an Australian population-based cohort with four examinations during a 15-year period (1992–1994 to 2007–2009) to determine whether regular aspirin use is associated with a higher risk of developing age-related macular degeneration (AMD).

They had participants complete a detailed questionnaire at baseline assessing aspirin use, cardiovascular disease status and AMD risk factors. The researchers graded AMD by comparing retinal photographs taken at each study visit to assess the incidence of neovascular, or wet, AMD and geographic atrophy, or dry AMD, according to the international AMD classification.

Of 2,389 baseline participants with follow-up data available, 257 individuals (10.8%) were regular aspirin users and 63 of the 2,389 developed neovascular AMD, the researchers reported. They noted that persons who were regular aspirin users were more likely to have incident neovascular AMD: the 15-year cumulative incidence was 9.3% in users and 3.7% in nonusers. After adjusting for age, sex, smoking, history of cardiovascular disease, systolic blood pressure and body mass index, they found that persons who were regular aspirin users had a higher risk of developing neovascular AMD (odds ratio [OR], 2.46; 95% CI, 1.25–4.83) and that the association showed a dose-response effect (multivariate-adjusted p=.01 for trend). Furthermore, the study researchers determined that aspirin use was not associated with the incidence of geographic atrophy (multivariate-adjusted OR, 0.99; 95% CI, 0.59–1.65).

Source: Liew G, Mitchell P, Wong TY, et al. The association of aspirin use with age-related macular degeneration. JAMA Intern Med. 2013; Jan 21. [Epub ahead of print]. DOI: 10.1001/jamainternmed.2013.1583.

Commentary on Liew, et al.

The Invited Commentary by cardiologists Sanjay Kaul, MD, and George A. Diamond, MD, takes a closer look at the prospective, population-based cohort study by Liew and colleagues (above) to determine whether the relationship of aspirin use with age-related macular degeneration (AMD) has to do with association or causation.

They point out strengths of the study, including the fact that it is the largest prospective cohort with more than five years of longitudinal evaluation reported to date using objective and standardized ascertainment of AMD, as well as the use of standardized protocols for determining medication use, the recording of detailed demographic and clinical information for risk adjustment, and appropriate methodologic approaches, such as multivariate logistic regression and propensity score adjustment, to minimize the impact of confounding. The key limitation, according to Kaul and Diamond, is the nonrandomized design of the study, with its potential for residual (unmeasured or unobserved) confounding that cannot be mitigated by multivariate logistic regression or propensity score analysis. Additional limitations they say deserve attention include the modest strength of association (odds ratio, 2.0–2.5); incomplete data on other morbidities; the potential for “overfitting” resulting in biased estimates because of the limited number of incident cases of AMD (n=63) and 10 or more candidate predictor variables; and the issue of missing data (only 56% of the cohort eligible for follow-up at >15 years were assessed). These limitations can potentially undermine the interpretation and threaten the validity of trial results.

Application of the Hill criteria to the Liew study yields instructive insights, according to Kaul and Diamond. These are useful and time-tested considerations for determining whether an association is causal. They look at strength of association, consistency, temporality, biological gradient or dose-response relationship, biological plausibility, specificity, coherence, experiment and analogy.

From a purely science-of-medicine perspective, they indicate that the strength of evidence is not sufficiently robust to be clinically directive and that at best, these findings are hypothesis-generating that should await validation in prospective, randomized studies before guiding clinical practice or patient behavior. However, from an art-of-medicine perspective, based on the limited amount of available evidence, some courses of action are available. In the absence of definitive evidence regarding whether limiting aspirin exposure mitigates AMD risk, one obvious course of action is to maintain the status quo; for primary prevention of cardiovascular disease, the decision to prescribe aspirin should be predicated on the balance of risks and benefits; and for guideline-eligible patients, the presence or absence of strong risk factors for neovascular AMD might tilt treatment decisions in one direction or the other. For patients taking long-term aspirin for other indications, such as pain control, caution is warranted in light of these observations.

In Kaul and Diamond's final analysis, they state that decisions about aspirin use are best made by balancing the risks against the benefits in the context of each individual’s medical history and value judgments.

Source: Kaul S, Diamond GA. Relationship of aspirin use with age-related macular degeneration. JAMA Intern Med. Jan 21. [Epub ahead of print]. DOI: 10.1001/jamainternmed.2013.2530.

Realizing the Limitations of Research Data

In an Editor's Note about the Invited Commentary by Kaul and Diamond, Kenneth E. Covinsky, MD, MPH, emphasizes the need for careful consideration before concluding that an association described in an observational study truly represents a cause-effect relationship. He noted that while the study by Liew, et al. may provide useful incremental data about an important condition, the data are not definitive enough to suggest changes in clinical practice. In fact, the purpose of covering such an article is to hopefully stimulate further research on the relationship between aspirin and macular degeneration. Dr. Covinsky notes that the Liew study provides an opportunity to educate the public about the subtleties and incremental nature of medical research and that our understanding of disease etiology advances as evidence accumulates from multiple good studies.

Source: Covinsky KE. The incremental nature of clinical research. JAMA Intern Med. 2013; Jan 21. [Epub ahead of print].

Relationship Between Long-term Aspirin Use and AMD

The Beaver Dam Eye Study, a longitudinal population-based study of age-related eye diseases conducted in Wisconsin, examined the association of regular aspirin use with incidence of age-related macular degeneration (AMD). Examinations were performed every five years over a 20-year period (1988 to 1990 through 2008 to 2010). Study participants (n=4,926) were aged 43 to 86 years at the baseline examination. At subsequent examinations, participants were asked if they had regularly used aspirin at least twice a week for more than three months. The main outcome measure was the incidence of early AMD, late AMD and two subtypes of late AMD (neovascular AMD and pure geographic atrophy), assessed in retinal photographs according to the Wisconsin Age-Related Maculopathy Grading System.

The mean duration of follow-up was 14.8 years and there were 512 incident cases of early AMD (of 6,243 person-visits at risk) and 117 incident cases of late AMD (of 8,621 person-visits at risk) over the course of the study. Regular aspirin use of 10 years prior to retinal examination was associated with late AMD (hazard ratio [HR], 1.63 [95% CI, 1.01–2.63]; p=.05), with estimated incidence of 1.76% (95% CI, 1.17%–2.64%) in regular users and 1.03% (95% CI, 0.70%–1.51%) in nonusers. It was noted that for subtypes of late AMD, regular aspirin use 10 years prior to retinal examination was significantly associated with neovascular AMD (HR, 2.20 [95% CI, 1.20–4.15]; p=.01) but not pure geographic atrophy (HR, 0.66 [95% CI, 0.25–1.95]; p=.45). Aspirin use five years (HR, 0.86 [95% CI, 0.71–1.05]; p=.13) or 10 years (HR, 0.86 [95% CI, 0.65–1.13]; p=.28) prior to retinal examination was not associated with incident early AMD.

Among an adult cohort, aspirin use five years prior to observed incidence was not associated with early or late AMD. However, regular aspirin use 10 years prior was associated with a small but statistically significant increase in the risk of incident late and neovascular AMD.

Source: Klein BE, Howard KP, Gangnon RE, et al. Long-term use of aspirin and age-related macular degeneration. JAMA. 2012;308(23):2469–2478.

Epimacular Brachytherapy in the Treatment of Neovascular AMD

To evaluate the safety and efficacy of epimacular brachytherapy (EMBT) for the treatment of neovascular age-related macular degeneration (AMD), the authors of this multicenter, randomized, active-controlled, Phase III clinical trial examined 494 participants with treatment-naïve neovascular AMD.

They randomized participants with classic, minimally classic, and occult lesions in a 2:1 ratio to EMBT or a ranibizumab monotherapy control arm. The EMBT arm received two mandated, monthly loading injections of 0.5 mg ranibizumab. The control arm received three mandated, monthly loading injections of ranibizumab, followed by quarterly injections. Both arms also received monthly as needed (pro re nata) retreatment. The proportion of participants losing fewer than 15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters from baseline visual acuity (VA) and the proportion gaining more than 15 ETDRS letters from baseline VA was the main outcome measure.

The authors reported that at 24 months, 77% of the EMBT group and 90% of the control group lost fewer than 15 letters. This difference did not meet the prespecified 10% noninferiority margin. Additionally, this end point was noninferior using a 20% margin and a 95% confidence interval for the group as a whole and for classic and minimally classic lesions, but not for occult lesions. The study authors also noted that EMBT did not meet the superiority end point for the proportion of participants gaining more than 15 letters (16% for the EMBT group versus 26% for the control group): this difference was statistically significant (favoring controls) for occult lesions, but not for predominantly classic and minimally classic lesions. They observed a mean VA change of –2.5 letters in the EMBT arm and +4.4 letters in the control arm. Participants in the EMBT arm received a mean of 6.2 ranibizumab injections versus 10.4 in the control arm. At least one serious adverse event occurred in 54% of the EMBT arm, most commonly postvitrectomy cataract, versus 18% in the control arm. Mild, nonproliferative radiation retinopathy occurred in 3% of the EMBT participants, but no case was vision-threatening.

In conclusion, the two-year efficacy data do not support the routine use of EMBT for treatment-naïve wet AMD, despite an acceptable safety profile. Further safety review is required.

Source: Dugel PU, Bebchuk JD, Nau J, et al; CABERNET Study Group. Epimacular brachytherapy for neovascular age-related macular degeneration: a randomized, controlled trial (CABERNET). Ophthalmology. 2013;129(2):317–327.

Macular Epiretinal Brachytherapy in Treated AMD

Investigators performed this prospective, multicenter, interventional, noncontrolled clinical trial to report the optical coherence tomography (OCT) and fundus fluorescein angiography (FFA) results of the Macular Epiretinal Brachytherapy in Treated Age-Related Macular Degeneration study.

Participants consisted of 53 eyes of 53 patients with chronic, active neovascular age-related macular degeneration (AMD) requiring frequent anti-vascular endothelial growth factor (anti-VEGF) retreatment. Participants underwent pars plana vitrectomy with a single 24-gray dose of epimacular brachytherapy (EMB), delivered with an intraocular, handheld cannula containing a strontium 90/yytrium 90 source positioned over the active lesion. The investigators retreated participants with ranibizumab administered monthly as needed, using predefined retreatment criteria. Patients underwent FFA at baseline, month one and month 12. They also underwent optical coherence tomography (OCT) at baseline and then monthly for 12 months. The FFA and OCT images were evaluated by independent, central reading facilities. Change in OCT centerpoint thickness and angiographic lesion size 12 months after EMB was the main outcome measure.

According to the investigators, mean centerpoint thickness increased by 50 µm, from 186 µm to 236 µm (p=0.292), but 70% of participants had an increase of less than the mean, with a median increase of only 1.8 µm. They reported that the FFA total lesion size increased slightly by 0.79 mm², from 14.69 mm² to 15.48 mm² (p=0.710) and that the total choroidal neovascularization (CNV) area increased by 1.17 mm², from 12.94 mm² to 14.12 mm² (p=0.556). They also found that the classic CNV area decreased substantially by 3.70 mm², from 3.90 mm² to 0.20 mm² (p<0.01). Predominantly classic lesions showed the greatest response, with mean Early Treatment Diabetic Retinopathy Study visual acuity improving by 1.5 letters (versus –4.0 for all participants combined); mean centerpoint thickness decreased by 43 µm (p=0.875). The angiographic and OCT response did not correlate with lesion size at baseline.

The study investigators concluded that in chronic, active neovascular AMD, EMB is associated with nonsignificant changes in centerpoint thickness and FFA total lesion size over 12 months.

Source: Petrarca R, Dugel PU, Nau J, et al. Macular epiretinal brachytherapy in treated age-related macular degeneration (MERITAGE): month 12 optical coherence tomography and fluorescein angiography. Ophthalmology. 2013;120(2):328–333.

Effect of 2.0 mg Intravitreal Ranibizumab on Recalcitrant Neovascular AMD

To determine whether a higher dose of intravitreal ranibizumab could improve the anatomy and best-corrected visual acuity (BCVA) in eyes with neovascular age-related macular degeneration (AMD) with persistent disease activity despite monthly intravitreal anti-vascular endothelial growth factor (VEGF) injections, this Phase I to II multicenter, open-label, controlled clinical trial was performed.

Participants included 87 patients with recalcitrant neovascular AMD, defined as having leakage on fundus fluorescein angiography or spectral domain optical coherence tomography (SD-OCT) despite frequent anti-VEGF injections. Each was treated with 2.0-mg ranibizumab injections monthly for three doses and monitored with Early Treatment Diabetic Retinopathy Study (ETDRS) 4-m refractions, clinical examinations and SD-OCT. Mean outcome measures were the mean change in baseline visual acuity (VA), the percentage of patients who experienced a loss or gain of 15 or more letters in ETDRS BCVA, the mean change in central retinal thickness and the incidence of adverse events.

A total of 87 patients with an average of 24 injections before enrollment and a mean of 10.4 injections in the preceding 12 months had a mean refracted VA of 69.2 ETDRS letters (20/41 Snellen) and a mean central subfield of 422 µm at baseline. Mean VA gain over baseline was +2.5 letters at day seven (n=82), +3.7 letters at month one (n=87), +3.9 letters at month two (n=87) and +3.3 letters at month three (20/36 Snellen; p=0.001; n=86). Furthermore, anatomic outcomes showed a mean OCT central subfield thickness improvement from baseline of –48.4 µm at day seven (n=84), –37.5 µm at month 1 (n=87), –42.4 µm at month two (n=85), and –33.1 µm at month three (p=0.01; n=86).

Intravitreal injections of 2.0 mg ranibizumab led to statistically significant VA gains and anatomic improvement in patients with persistent intraretinal, subretinal or subretinal pigment epithelial fluid during a previous regimen of frequent 0.5-mg ranibizumab injections.

Source: Brown DM, Chen E, Mariani A, Major JC, SAVE Study Group. Super-dose anti-VEGF (SAVE) trial: 2.0 mg intravitreal ranibizumab for recalcitrant neovascular macular degeneration–primary end point. Ophthalmology. 2013;120(2):349–354.

Progression of Intermediate AMD With Proliferation and Inner Retinal Migration of Hyper-reflective Foci

Drusen and migrating retinal pigment epithelium have been associated with hyper-reflective foci (HF) detected by spectral-domain optical coherence tomography (SD-OCT). This study sought to quantify the change in intraretinal HF distribution and its correlation with age-related macular degeneration (AMD) progression.

This prospective, observational study from the multicenter Age-Related Eye Disease Study 2 (AREDS2) Ancillary SD-OCT Study included patients (n=299) with one enrolled eye with intermediate AMD and baseline SD-OCT, followed by SD-OCT imaging at one- and two-year visits. The number and location of HF were scored in SD-OCT scans of all 299 eyes and the change in transverse (horizontal) and axial (vertical) distribution of HF in the macula were evaluated with pairwise signed-rank tests. Two-year inner retinal HF migration was determined by the change in HF-weighted axial distribution (AxD) score calculated for each eye. The correlation of HF with SD-OCT features of AMD progression was evaluated with logistic regression analysis. The main outcome measure was the mean change in number of HF, transverse and axial distribution of HF in the macula, and AxD per eye.

In 299 study eyes, the two-year increase in the number of HF (p<0.001) and the AxD (p<0.001) per eye represented longitudinal proliferation and shift to inner retinal layers, respectively. Eyes with geographic atrophy (GA) at two years were correlated with the presence of baseline HF (p<0.001; odds ratio [OR], 4.72; 95% confidence interval [CI], 2.43–9.80), greater number of baseline HF (p<0.001; OR, 1.61 per HF; 95% CI, 1.32–2.00) and greater baseline AxD (p<0.001; OR, 1.58 per AxD point; 95% CI, 1.29–1.95).

Proliferation and inner retinal migration of SD-OCT HF occurred during follow-up in eyes with intermediate AMD. These characteristics were associated with greater incidence of GA at year two; therefore, SD-OCT HF proliferation and migration may serve as biomarkers for AMD progression.

Source: Christenbury JG, Folgar FA, O’Connell RV, et al; Age-Related Eye Disease Study 2 Ancillary Spectral Domain Optical Coherence Tomography Study Group. Progression of intermediate age-related macular degeneration with proliferation and inner retinal migration of hyperreflective foci. Ophthalmology. 2013; Jan 24. [Epub ahead of print]. DOI: 10.1016/j.ophtha.2012.10.018.

ARMS2 and the Risk of Early and Late AMD

In the following population-based, cross-sectional European Eye Study in seven countries in Europe, scientists examined associations between severity stages of early and late age-related macular degeneration (AMD) and genetic variations in age-related maculopathy susceptibility 2 (ARMS2) and complement factor H (CFH) and investigated potential interactions between smoking and ARMS2.

They recruited 4,750 participants, 65 years of age and older, through random sampling. They classified participants on the basis of the more severely affected eye into five mutually exclusive AMD severity stages ranging from no AMD, three categories of early AMD and late AMD. History of cigarette smoking was available and allowed classification into never, former and current smokers, with the latter two groups combined into a single category of ever smokers for analysis. The scientists also performed genotyping for single nucleotide polymorphisms rs10490924 and rs4146894 in ARMS2 and rs1061170 in CFH and analyzed these associations by logistic regression. Main outcome measures consisted of odds ratios (ORs) for stage of AMD associated with genetic variations in ARMS2 and CFH and interactions between ARMS2 and smoking status.

Early AMD was present in 36.4% and late AMD was present in 3.3% of participants, the study scientists found. Data on both genotype and AMD were available for 4,276 people. The ORs for associations between AMD stage and ARMS2 increased monotonically with more severe stages of early AMD and were altered little by adjustment for potential confounders. Compared with persons with no AMD, carriers of the TT genotype for rs10490924 in ARMS2 had a 10-fold increase in risk of late AMD (p<3×10–20). The ORs for associations with CFH were similar for stage three early AMD and late AMD. Interactions between rs10490924 in ARMS2 and smoking status were significant in both unadjusted and adjusted models (p=0.001). The scientists noted that the highest risk was observed in those doubly homozygous for rs10490924 and rs1061170 in CFH (OR, 62.3; 95% confidence interval, 16–242), with p values for trend ranging from 0.03 (early AMD, stage 1) to 1×10–26 (late AMD).

A strong association was demonstrated between all stages of AMD and genetic variation in ARMS2, and a significant gene-environment interaction with cigarette smoking was confirmed.

Source: Chakravarthy U, McKay GJ, de Jong PT, et al. ARMS2 increases the risk of early and late age-related macular degeneration in the European Eye Study. Ophthalmology. 2013;120(2):342–348.

Argon Laser With and Without Anti-VEGF Therapy for Extrafoveal PCV

In Singapore, the following prospective cohort, noninterventional study sought to describe the clinical characteristics and outcome of eyes with extrafoveal polypoidal choroidal vasculopathy (PCV) treated with argon laser.

This was a prospective study of Asian patients with extrafoveal PCV, confirmed on indocyanine green angiography and treated with argon laser with and without anti-vascular endothelial growth factor (VEGF) therapy. Patients were followed over 12 months with visual, angiographic and structural outcomes recorded.

Of the 93 eyes with PCV at baseline, 33 eyes (35.5%) in 31 patients had extrafoveal involvement and were treated with argon laser. Foveal involvement with fluid or blood at baseline was apparent in 23 eyes (69.7%), despite the extrafoveal location of one or more polyps. Of these 33 eyes, 12 (36.4%) also received anti-VEGF injections (median, 2.5 injections) over the 12-month period. Two eyes received photodynamic therapy rescue during subsequent follow-up and were excluded for visual outcome analysis. In the remaining 31 eyes, mean visual acuity improved from 0.57 logarithm of the minimal angle of resolution (logMAR) units (range, 0.00 to 2.0 logMAR; standard deviation, 0.51 logMAR) at baseline to 0.39 logMAR (range, 0.00 to 2.0 logMAR; standard deviation, 0.43 logMAR) at month 12 (p=.01), with a mean gain in visual acuity of 9.0 letters at month 12. Stable or improved vision (defined as losing five letters or fewer) was achieved in 28 eyes (90.3%). Use of anti-VEGF was associated with significantly thicker central subfield at baseline (347.6 vs. 258.1 µm; p=.02) and resulted in similar vision and OCT results at month three and 12 compared with eyes that did not receive anti-VEGF.

It was concluded that argon laser treatment with selected use of anti-VEGF therapy achieves stable or improved visual outcome in most eyes with extrafoveal PCV, including eyes with fluid or blood affecting the fovea at presentation.

Source: Cheung CM, Yeo I, Li X, et al. Argon laser with and without anti-vascular endothelial growth factor therapy for extrafoveal polypoidal choroidal vasculopathy. Am J Ophthalmol. 2013;155(2):295–304.

Treatment of Myopic CNV With Intravitreal Pegaptanib Sodium (Macugen)

The authors of the following open-label, nonrandomized, prospective clinical trial reported the morphologic and functional outcomes resulting from the use of intravitreal pegaptanib sodium (Macugen) in patients with myopic choroidal neovascularization (CNV).

They assessed morphologic outcome, such as foveal thickness, by optical coherence tomography (OCT), and functional outcomes by best-corrected visual acuity (BCVA) and microperimetry. Their treatment protocol consisted of three consecutive doses of intravitreal pegaptanib (0.3 mg/0.05 mL; baseline, sixth week, and 12th week). Follow-up checks were scheduled at baseline, 18, 24, 36 and 48 weeks.

The authors studied 20 eyes from 20 patients; all patients completed follow-up at 48 weeks. After intravitreal pegaptanib, a significant decrease in foveal thickness occurred (–20%), and at the end of follow-up, CNV closure was obtained in all eyes. The study authors recorded an improvement of functional parameters in all patients (BCVA from 25.5 ± 8.09 letters to 45.5 ± 8.16 letters, p<0.0001; microperimetry from 8.40 ± 2.14 dB to 10.8 ± 2.05 dB, p<0.01). They noted that the mean number of intravitreal pegaptanib doses was three, and that none of patients met the re-treatment criterion during the entire follow-up period. Neither ocular nor systemic side effects were observed.

The findings demonstrate that the selective inhibition of VEGF-165 isoform by IVP is an effective treatment for myopic choroidal neovascularization.

Source: Rinaldi M, Chiosi F, Dell'omo R, et al. Intravitreal pegaptanib sodium (Macugen) for treatment of myopic choroidal neovascularization: a morphologic and functional study. Retina. 2013;33(2):397–402.

10-year Incidence and Risk Factors for RVO

The researchers in this population-based, longitudinal study sought to assess the 10-year incidence of retinal vein occlusions (RVOs) and associated factors in adult Chinese subjects.

Participants consisted of 2,695 subjects from the 2001 Beijing Eye Study (66.4% of the survivors), when repeated in 2011. The study participants underwent a detailed ophthalmic examination. The researchers reviewed the fundus photographs for the new development of RVOs and differentiated these into branch RVOs (BRVOs) and central RVOs (CRVOs). The main outcome measure was incidence of RVOs.

The study researchers detected incident RVOs in 51 eyes (49 subjects) with an incidence of 1.9 ± 0.1 per 100 persons and 1.0 ± 0.1 per 100 eyes. They reported that the incidence of BRVO was 1.6 ± 0.1 per 100 subjects (43 subjects [88% of patients with RVO]; 44 eyes), and incidence of CRVO was 0.3 ± 0.1 per 100 persons. Of 61 patients with an RVO in 2001 and 25 subjects reexamined in 2011, at least four subjects (7%) developed a second RVO. Incident BRVOs were located more often in the superior temporal quadrant and inferior temporal quadrant (32% and 34%, respectively) than in the superior nasal quadrant and inferior nasal quadrant (21% and 14%, respectively), the researchers noted. They also determined that in 35 eyes (80% of the BRVO eyes), the BRVO was located at an arteriovenous crossing. At the crossing sites, they found arterioles superficial to venules in 28 eyes (64% of the BRVO eyes) and they detected macular edema in 18 (37%) of all RVO eyes, including 13 (30%) of BRVO eyes. In multivariate logistic analysis, they associated incident RVOs with higher systolic blood pressure (p=0.01; odds ratio [OR], 1.04), hypertension (p=0.03; OR, 4.62), lower cognitive function score (p=0.007; OR, 0.88), blood concentration of cholesterol ≥5.72 mmol/L (p=0.007; OR, 3.29) and status after cerebral infarction/hemorrhage (p=0.02; OR, 1.19). Incident RVOs were not significantly related to the intake of aspirin (p=0.37).

The 10-year incidence of RVOs in Greater Beijing (1.9 ± 0.1 per 100 persons) was similar to that in other studies on Caucasian populations. The 10-year incidence of RVOs was related to the known risk factors of arterial hypertension, hypercholesterolemia and status after cerebral infarction/hemorrhage, as well as with a lower cognitive function score. Incident BRVO was approximately six times more frequent than incident CRVO and macular edema was detected in approximately 30% of BRVO eyes.

Source: Zhou JQ, Xu L, Wang S, et al. The 10-year incidence and risk factors of retinal vein occlusion: The Beijing Eye Study. Ophthalmology. Jan 24. [Epub ahead of print]. DOI: 10.1016/j.ophtha.2012.09.033.

Natural Course, Intravitreal Triamcinolone, and Intravitreal Bevacizumab for Treatment of Macular Edema Secondary to BRVO

To evaluate the natural course of the eyes with macular edema secondary to branch retinal vein occlusion (BRVO) and to compare the visual outcome and macular thickness with eyes treated with intravitreal injection of triamcinolone acetonide (IVTA) and intravitreal injection of bevacizumab (IVB), the authors of this Korean study reviewed the medical records of patients with macular edema secondary to BRVO who were followed over 12 months.

They evaluated the best-corrected visual acuity (BCVA) and central macular thickness (CMT) of the patients who have had no treatment for macular edema (natural course group) and compared the BCVA and CMT of the patients who had been treated with IVTA or IVB.

BCVA and CMT of the natural course group improved in a slow, but steady manner, the authors found. They also noted that the IVTA and the IVB group showed temporary improvement after injection, but macular edema recurred and there was no significant difference in the visual outcome and macular thickness after six months.

To conclude, although IVTA and IVB were effective to decrease the macular edema at one month after the injection in BRVO, BCVA and CMT of the natural course group were not inferior to both the IVTA and the IVB groups at 12 months.

Source: Kwon SI, Kim YW, Bang YW, et al. Comparison of natural course, intravitreal triamcinolone, and intravitreal bevacizumab for treatment of macular edema secondary to branch retinal vein occlusion. J Ocul Pharmacol Ther. 2013;29(1):5–9.

Analysis of Risk Factors Linked to CRVO

To identify risk factors associated with central retinal vein occlusion (CRVO) among a diverse group of patients throughout the United States, investigators conducted this longitudinal cohort study.

In their study, they included all beneficiaries aged ≥55 years who were continuously enrolled in a managed care network for at least two years and who had two or more visits to an eyecare provider from 2001 to 2009.

The investigators used insurance billing codes to identify individuals with a newly diagnosed CRVO. They performed multivariable Cox regression to determine the factors associated with CRVO development. Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) of being diagnosed with CRVO served as the main outcome measures.

Of the 494,165 enrollees who met the study inclusion criteria, 1,302 (0.26%) were diagnosed with CRVO over 5.4 (± 1.8) years. After adjustment for known confounders, the investigators found that blacks had a 58% increased risk of CRVO compared with whites (HR, 1.58; 95% CI, 1.25–1.99), and that women had a 25% decreased risk of CRVO compared with men (HR, 0.75; 95% CI, 0.66–0.85). A diagnosis of stroke increased the hazard of CRVO by 44% (HR, 1.44; 95% CI, 1.23–1.68), and hypercoagulable state was associated with a 145% increased CRVO risk (HR, 2.45; 95% CI, 1.40–4.28). Individuals with end-organ damage from hypertension (HTN) or diabetes mellitus (DM) had a 92% (HR, 1.92; 95% CI, 1.52–2.42) and 53% (HR, 1.53; 95% CI, 1.28–1.84) increased risk of CRVO, respectively, relative to those without these conditions.

This study confirms that HTN and vascular diseases are important risk factors for CRVO. The study investigators also identify black race as being associated with CRVO, which was not well appreciated previously. Furthermore, they show that, compared with patients without DM, individuals with end-organ damage from DM have a heightened risk of CRVO, whereas those with uncomplicated DM are not at increased risk of CRVO. This finding may provide a potential explanation for the conflicting reports in the literature on the association between CRVO and DM. Information from analyses such as this can be used to create a risk calculator to identify possible individuals at greatest risk for CRVO.

Source: Stem MS, Talwar N, Comer GM, Stein JD. A longitudinal analysis of risk factors associated with central retinal vein occlusion. Ophthalmology. 2013; 120(2):362–370.

Efficacy of Intravitreal Bevacizumab for Acute CSCR

The following study investigated the efficacy of intravitreal bevacizumab injection in patients with acute central serous chorioretinopathy (CSCR).

Between six weeks and three months, 13 eyes of 22 patients with acute CSCR received an intravitreal bevacizumab injection (2 mg/0.08 mL); nine eyes had no medical treatment as a control. At baseline and follow-up visits, patients had best-corrected visual acuity (BCVA), intraocular pressure assessment, dilated fundus examination and spectral domain optical coherence tomography (SD-OCT) imaging. Outcome measures were the resolution of neurosensory detachment, improvement in visual acuity and symptoms.

All patients showed prompt improvements of visual acuity and symptoms until the third month and recovered from neurosensory detachment gradually following treatment in the study group. It was reported that the vision of control subjects recovered later and that the regression of serous retinal detachments was fairly slow. It was also noted that the mean BCVA improved from 0.39 ± 0.16 at first visit (at baseline) to 0.73 ± 0.17 at the sixth month in the study group and from 0.25 ± 0.17 at first visit (at baseline) to 0.67 ± 0.13 at the sixth month in the control group, which was statistically significant (p=0.0001; p=0.0001, respectively). Mean retinal thickness for the study group was decreased from 414.38 ± 102.79 at first visit (at baseline) to 256.46 ± 84.77 at the third month and 198.30 ± 29.81 at the sixth month (p=0.0001, p=0.0001). For the control group, mean retinal thickness was decreased from 510.33 ± 80.59 at first visit (at baseline) to 336.33 ± 127.83 at the third month and 205.66 ± 19.65 at the sixth month (p=0.004, p=0.0001, respectively). Furthermore, one of the patients in the control group revealed recurrence at the sixth month and the patient was given intravitreal injection of bevacizumab.

It was concluded that intravitreal bevacizumab injection for acute CSCR can lead to remarkable improvements of visual acuity within three months follow-up compared to controls. These results demonstrated that intravitreal bevacizumab injection may be a promising option for selected patients in the treatment of acute CSCR.

Source: Aydin E. The efficacy of intravitreal bevacizumab for acute central serous chorioretinopathy. J Ocul Pharmacol Ther. 2013;29(1):10–13.

Choroidal Thickness in CSCR

Researchers studied the choroidal thickness profile of 35 eyes (27 patients) with central serous chorioretinopathy (CSCR) and 35 healthy, age-matched control eyes using high-penetration optical coherence tomography (OCT).

They observed the choroid using the prototype high-penetration OCT and performed fluorescein angiography and indocyanine green angiography to identify the CSCR location and activity. They also manually measured choroidal thicknesses in various conditions or locations. The choroidal thickness maps were obtained from cube scans and calculating software and composed of nine sectors in the Early Diabetic Retinopathy Study chart.

According to the researchers, the subfoveal choroidal thicknesses in all eyes with CSCR were significantly (p<0.01) greater than that in the control eyes. They noted that the choroidal thickness at the fovea and the fluorescein points of leakage were significantly (p<0.01 for both comparisons) greater in eyes with CSCR than the corresponding locations in the fellow eyes in patients with unilateral disease. They also observed that dilatation of the choroidal large vessels was significantly (p<0.01) more common in CSCR. The foveal choroidal thickness was significantly greater in eyes with venous dilatation (p<0.01) than those without, the study researchers determined. They reported that the mean choroidal thickness was significantly (p<0.05) greater in all sectors of the Early Diabetic Retinopathy Study chart except for the inner (p=0.087) and outer (p=0.053) inferior sectors. Moreover, the percent mean choroidal thicknesses compared with the normal controls in the nasal sector were significantly (p<0.05 and p<0.01, respectively) greater in the inner and outer circles than in the superior, temporal and inferior sectors.

The choroid is diffusely thickened in CSCR likely because of the choroidal vascular dilatation. The nasal macula undergoes the greatest alterations in choroidal thickness compared with the other areas.

Source: Kuroda S, Ikuno Y, Yasuno Y, et al. Choroidal thickness in central serous chorioretinopathy. Retina. 2013;33(2):302–308.

Use of PDT for Chronic CSCR

In this retrospective, multicenter, interventional case series analysis, scientists evaluated the efficacy and safety of standard photodynamic therapy (PDT) with verteporfin at 48 months in patients with chronic central serous chorioretinopathy (CSCR).

They evaluated patients every three months in the first year, every six months in the second year and thereafter annually. They performed optical coherence tomography (OCT) at all visits but fluorescein angiography and indocyanine green angiography at baseline and thereafter as necessary. They also manually measured retinal thickness on OCT, evaluating central macular thickness and neural retina thickness. Main outcomes included the evolution of best-corrected visual acuity (BCVA); the resolution of subretinal fluid, documented with OCT; the number of treatments; and the evaluation of neural retina thickness during the 48 months of follow-up.

The study included 46 eyes of 42 patients, 38 men (90.4%) and four women (9.5%), with mean age of 49.19 ± 9.9 years (range, 32–70 years). The minimum follow-up period was 48 months (mean, 56.8 ± 10.3 months). The scientists observed subretinal fluid in all of the included eyes at baseline and 10 eyes (21.7%) had intraretinal diffuse or cystoid fluid. Concerning the mean BCVA, they reported that a statistically significant improvement (p<0.01, Student t-test) was registered from 58.8 ± 18.3 letters at baseline to 66.9 ± 18.6 letters at the 48th month. A complete resolution of subretinal fluid was achieved in 93.4%, and resolution of intraretinal fluid occurred in all 10 cases at 48 months. Additionally, neural retina thickness remained stable during the 48 months of follow-up (163.8 ± 47 µm at baseline and 163.8 ± 46 µm at 48 months). The mean number of treatments was 1.08 ± 0.3 and no systemic or ocular side effects were registered.

In conclusion, standard PDT with verteporfin was effective and safe in chronic CSCR treatment with a significant improvement in the long term, both anatomic and visual, without inducing additional retinal atrophy or systemic adverse effects.

Source: Silva RM, Ruiz-Moreno JM, Gomez-Ulla F, et al. Photodynamic therapy for chronic central serous chorioretinopathy: a 4-year follow-up study. Retina. 33(2):309–315.

FDA Accepts IND for Optina to Treat DME

The FDA has accepted Ampio Pharmaceuticals Inc.'s IND for Optina for the treatment of diabetic macular edema (DME). The drug is based on a low dose of the weak androgen, low molecular weight, very lipophilic steroid danazol. The FDA granted Optina 505(b)(2) status last year; drugs designated under this pathway can be approved on a single trial. Ampio plans to commence enrollment in a clinical trial in the first quarter of 2013. The trial is designed to evaluate the safety and efficacy of oral Optina compared with placebo given over a period of 12 weeks in adult patients with DME. Patients will be randomized to receive one of two doses of Optina (0.5 mg per BMI and 1.0 mg per BMI per day) or placebo. The primary endpoint is improvement in visual acuity (VA). Secondary endpoints include measurements of changes in VA and central macular thickness in treated patients compared to placebo, as well as safety and tolerability of the two Optina doses.

Source: Ampio Pharmaceuticals Inc., January 2013.

New Line of Vitreoretinal Devices and Instruments From FCI Ophthalmics

FCI Ophthalmics has introduced a new line of devices and instruments designed to provide retina surgeons with high-performance products for vitreoretinal procedures. The products begin with a wide selection of disposable laser probes, fiber optic probes and laser illumination sources that can connect to any manufacturer's vitreoretinal power supply, but a range of instruments and hand-pieces made from lightweight and durable titanium in several gauges are also available, including Retilock, a one-step, self-retaining trocar system for easy access to the posterior segment. Other products in the vitreoretinal launch include: single-use and reusable backflush handles and reservoirs for passive and active aspiration; disposable PFCL and subretinal cannulas, scleral buckling components, vitrectomy lenses and Invitria – Intravitreal Injection Assistant. Additional information can be obtained by calling (800) 932-4202 or by emailing info@fci-ophthalmics.com.

Source: FCI Ophthalmics, January 2013.

Santen and Clearside Enter Into Agreements for Posterior Ocular Disease

Santen Inc. and Clearside Biomedical Inc. recently announced that Santen Ltd., the parent company of Santen Inc., has made an investment in Clearside Biomedical Inc. and has also entered into a research collaboration agreement for posterior ocular diseases. Santen will join with other investors to fund an additional $7.9 million for continued development of CLS1001 (triamcinolone acetonide) Suprachoroidal Injectable Suspension into pivotal testing and to further Clearside Biomedical's pipeline in ocular choroidal neovascularization and inflammatory diseases of the posterior segment. The FDA has allowed Clearside Biomedical to pursue testing related to the company's Investigational New Drug (IND) Application for CLS1001, which would treat sympathetic ophthalmia, temporal arteritis, uveitis and ocular inflammatory conditions unresponsive to topical corticosteroids. Clinical testing is scheduled to proceed in the first quarter of 2013. Click here for additional information.

Source: Clearside Biomedical Inc., January 2013.

NICE Publishes Final Guidance on Iluvien for DME

pSivida Corp. recently reported that the United Kingdom's National Institute for Health and Clinical Excellence (NICE) has published final guidance indicating that Iluvien is not cost effective for the treatment of chronic diabetic macular edema (DME) considered insufficiently responsive to available therapies. This final guidance is consistent with the final draft guidance issued on November 29, 2012. pSivida's licensee for Iluvien for DME, Alimera Sciences Inc., reported that it will pursue a Patient Access Scheme (PAS) for Iluvien for DME that is intended to allow treatment decisions to be based on patient need, rather than cost. According to Alimera, the PAS is currently under review by the Patient Access Schemes Liaison Unit at NICE. If approved by the Department of Health, the PAS will be available to the Appraisal Committee for review and consideration. Read more here.

Source: pSivida Corp., January 2013.


Review of Ophthalmology's® Retina Online is published by the Professional Publications Division of Jobson Medical Information LLC (JMI), 11 Campus Boulevard, Newtown Square, PA 19073.

To subscribe to other JMI newsletters or to manage your subscription, click here.

To change your email address, reply to this email. Write "change of address" in the subject line. Make sure to provide us with your old and new address.

To ensure delivery, please be sure to add reviewophth@jobsonmail.com to your address book or safe senders list.

Click here if you do not want to receive future emails from Review of Ophthalmology's Retina Online.