Graves Joins Glaucoma Research Foundation Board The Glaucoma Research Foundation recently reported that Adrienne L. Graves, PhD, president and CEO of Santen, Inc., has been appointed to its Board of Directors. First Neovascular AMD Patient Treated with Vidion ANV Therapy System in Europe, Enrollment Complete for Neovascular AMD Study According to a NeoVista, Inc. press release, the first European patients have been treated with the Vidion ANV Therapy System, the company's novel device for treating neovascular AMD. Aerie Pharmaceuticals' AR-12286 Found Safe and Well-Tolerated in Phase 2a Glaucoma Study Aerie Pharmaceuticals has announced positive results from a Phase 2a study of its Rho-kinase (ROCK) inhibitor, AR-12286... Novel Glaucoma Treatment Receives CE Approval IOPtima of the Israeli-based Bio-Light group has announced that it has received CE approval for its OT-134 Laser-based system...

Link Between Statin Use and Incidence of Advanced AMD

This cohort study within a multicenter, randomized, clinical trial evaluated the impact of statin use on the incidence of advanced age-related macular degeneration (AMD) and its components, choroidal neovascularization (CNV) and geographic atrophy (GA), among patients with bilateral large drusen. Participants consisted of patients enrolled in the Complications of Age-related macular degeneration Prevention Trial (CAPT).

Eligibility critera for the clinical trial required that participants have ≥10 large (>125 µm) drusen and visual acuity ≥20/40 in each eye. Patients scheduled for their final CAPT visit after May 2005 were interviewed on their history of use of cholesterol-lowering medications, including statins, and trained readers identified CNV and endpoint GA (>1 Macular Photocoagulation Study disc area of GA) based on review of fluorescein angiograms and fundus photographs taken at annual follow-up visits and when patients reported symptoms. The risk ratio for participants developing CNV or developing GA associated with statin use was estimated with time-dependent Cox proportional hazards models. Main outcome measures were the development of advanced AMD, CNV and endpoint GA.

It was observed that among 764 patients eligible for the interview, 744 (97.4%) patients completed the interview on medication use. Statin use was reported by 296 (39.8%) of those interviewed, with the majority, 187 (63.2%) of the 296, beginning use after enrollment in CAPT. Among 744 patients, advanced AMD developed in 332 (22.5%) eyes of 242 (32.5%) patients, CNV in 222 (15%) eyes of 176 (23.7%) patients, and GA in 114 (7.7%) eyes of 80 (10.8%) patients. With adjustment for other risk factors, the estimated risk ratio for eyes (95% confidence interval) associated with statin use was 1.15 (0.87-1.52) for advanced AMD, 1.35 (0.99-1.83) for CNV and 0.80 (0.46-1.39) for GA.

In conclusion, the CAPT data are not consistent with a strong protective effect (risk ratio, ≤0.85) of statins on the development of advanced AMD among patients with bilateral large drusen.

Source: Maguire MG, Ying G, McCannel CA, et al; Complications of Age-Related Macular Degeneration Prevention Trial (CAPT) Research Group. Statin use and the incidence of advanced age-related macular degeneration in the Complications of Age-Related Macular Degeneration Prevention Trial. Ophthalmol 2009;Oct 22 [Epub ahead of print] DOI: 10.1016/j.ophtha.2009.06.055.

Intravitreal Bevacizumab for Neovascular AMD: Visual Outcomes and Growth Factor Changes

To evaluate the visual and growth factor changes of two different intravitreal bevacizumab dosages for neovascular age-related macular degeneration, investigators randomized 50 eyes of 50 patients with neovascular age-related macular degeneration to received 3 monthly intravitreal injections of 1.25 mg (24 eyes) or 2.5 mg (26 eyes) bevacizumab. They observed patients for 6 months, and observed the logarithm of minimal angle of resolution best-corrected visual acuity, central foveal thickness, aqueous endothelial growth factor and pigment epithelial derived factor levels.

The investigators observed that both groups had significant central foveal thickness reductions at 6 months (p<0.001) and that six (23.1%) eyes in the 2.5-mg group lost 3 or more lines compared with none in the 1.25-mg group (p=0.023). They found no significant difference in logarithm of minimal angle of resolution best-corrected visual acuity, central foveal thickness or growth factors between the two groups at all visits. Moreover, eyes with persistent angiographic leakage at 3 months had significantly higher baseline aqueous vascular endothelial growth factor levels compared with eyes without leakage (p=0.013). Logistic regression analysis showed that high baseline aqueous vascular endothelial growth factor level was the only significant factor associated with persistent leakage at 3 months (p=0.040).

Three monthly intravitreal 1.25-mg bevacizumab injections seemed to result in better visual outcome than 2.5 mg bevacizumab, concluded the investigators. They added that baseline aqueous vascular endothelial growth factor level might have a role in predicting angiographic response after bevacizumab injections.

Source: Lai TY, Liu DT, Chan KP, et al. Visual outcomes and growth factor changes of two dosages of intravitreal bevacizumab for neovascular age-related macular degeneration: a randomized, controlled trial. Retina 2009;29(9):1218-1226.

Visual Acuity in AMD Patients After Cataract Surgery

The authors of this cohort study evaluated visual acuity outcomes after cataract surgery in patients with varying degrees of age-related macular degeneration (AMD). Participants consisted of 4,757 patients enrolled in the Age-Related Eye Disease Study (AREDS), which is a prospective, multicenter, epidemiological study of the clinical course of cataract and AMD and a randomized, controlled trial of antioxidants and minerals.

The authors took standardized lens and fundus photographs at baseline and annual visits and graded them by a centralized reading center using standardized protocols for severity of AMD and lens opacities. They obtained history of cataract surgery every 6 months and conducted analyses using multivariate logistic regression. The main outcome measure was the change in best-corrected visual acuity (BCVA) after cataract surgery compared with preoperative BCVA.

The study authors analyzed visual acuity results for 1,939 eyes that had cataract surgery during AREDS and they found that the mean time from cataract surgery to measurement of postoperative BCVA was 6.9 months. After adjustment for age at surgery, gender, type and severity of cataract, the mean change in visual acuity at the next study visit after the cataract surgery was as follows: eyes without AMD gained 8.4 letters of acuity (p<0.0001), eyes with mild AMD gained 6.1 letters of visual acuity (p<0.0001), eyes with moderate AMD gained 3.9 letters (p<0.0001) and eyes with advanced AMD gained 1.9 letters (p=0.04). The authors noted that the statistically significant gain in visual acuity after cataract surgery was maintained an average of 1.4 years after cataract surgery.

On average, participants with varying severity of AMD benefited from cataract surgery with an increase in visual acuity postoperatively. This average gain in visual acuity persisted for at least 18 months, the authors reported.

Source: Forooghian F, Agrón E, Clemons TE, et al, AREDS Research Group. Visual acuity outcomes after cataract surgery in patients with age-related macular degeneration: age-related eye disease study report no. 27. Ophthalmol 2009;116(11):2093-2100.

Treating Neovascular AMD with PDT and Intravitreal Triamcinolone

Researchers in this multi-center, 2-year, double-blind, randomized, sham-controlled trial conducted at 11 sites in Canada evaluated the efficacy of intravitreal triamcinolone acetonide (ITA) as an adjunct to photodynamic therapy with verteprofin (VPDT) in the treatment of predominantly classic, subfoveal choroidal neovascularization (CNV) owing to age-related macular degeneration (AMD). They randomized 100 individuals over the age of 50 1:1 to either VPDT alone or combined VPDT and ITA. All participants received full-fluence VPDT and were randomly assigned to either (1) a same-day injection of 4 mg ITA or (2) a sham intraocular injection. The change in numbers of letters read between baseline and 1 year was the primary endpoint in this study.

The researchers observed that combination therapy with VPDT and ITA, when compared with VPDT therapy alone, resulted in no significant difference in final visual acuity at 1 year. Eyes treated with combination therapy lost an average of 17 letters compared with 20 letters for the VPDT group. Additionally, subjects receiving ITA required significantly fewer retreatments over the course of the study (1.28 vs 1.94, respectively; p=0.003) and although elevated IOPs were noted in a larger proportion of subjects receiving ITA, all of these individuals were managed successfully with topical ocular antihypertensive agents.

There was no visual benefit to the addition of intravitreal triamcinolone to VPDT, the study researchers concluded. Combination therapy, however, can reduce the number of VPDT treatments required by subjects who have predominantly classic CNV owing to AMD. This reduced treatment quantity needs to be weighed against potential side effects.

Source: Maberley D, Canadian Retinal Trials Group. Photodynamic therapy and intravitreal triamcinolone for neovascular age-related macular degeneration: a randomized clinical trial. Ophthalmol 2009;116(11):2149-2157.

Systemic and Ophthalmic Abnormalities Association with Retinal Artery Occlusion

To investigate systematically the various associated systemic and ophthalmic abnormalities in different types of retinal artery occlusion (RAO), researchers included 439 consecutive untreated patients (499 eyes) with RAO first seen in their clinic from 1973 to 2000 in this cohort study.

At first visit, all patients underwent detailed ophthalmic and medical history as well as comprehensive evaluation. The researchers conducted visual evaluations by recording visual acuity, using the Snellen visual acuity chart and visual fields with a Goldmann perimeter and initially, the patients also had carotid Doppler/angiography and echocardiography. The same ophthalmic evaluation was performed at each follow-up visit and demographic features, associated systemic and ophthalmic abnormalities and sources of emboli in various types of RAO were the main outcome measures.

The study researchers classified RAO into central (CRAO) and branch (BRAO) artery inclusion and in both nonarteritic (NA) CRAO and BRAO, the prevalence of diabetes mellitus, arterial hypertension, ischemic heart disease and cerebrovascular accidents were significantly higher compared with the prevalence of these conditions in the matched U.S. population (all p<0.0001). They noted that smoking prevalence, compared with the U.S. population, was significantly higher for males (p=0.001) with NA-CRAO and for women with BRAO (p=0.02). Additionally, ipsilateral internal carotid artery had ≥50% stenosis in 31% of NA-CRAO patients and 30% of BRAO, and plaques in 71% of NA-CRAO and 66% of BRAO. An abnormal echocardiogram with an embolic source was seen in 52% of NA-CRAO and 42% of BRAO. Furthermore, neovascular glaucoma developed in only 2.5% of NA-CRAO eyes.

According to the researchers, this study showed that, in CRAO as well as in BRAO, the prevalence of various cardiovascular diseases and smoking was significantly higher compared with the prevalence of these conditions in the matched U.S. population. Embolism is the most common cause of CRAO and BRAO; plaque in the carotid artery is usually the source of embolism and less commonly the aortic and/or mitral valve. The presence of plaques in the carotid artery is generally of much greater importance than the degree of stenosis in the artery. The researchers reported that, contrary to the prevalent misconception, they found no cause-and-effect relationship between CRAO and neovascular glaucoma.

Source: Hayreh SS, Podhajsky PA, Zimmerman MB. Retinal artery occlusion: associated systemic and ophthalmic abnormalities. Ophthalmol 2009;116(10):1928-1936.

12-Month Results of Treatment with Intravitreal Injection of Bevacizumab for Macular Edema Secondary to BRVO

This study was conducted to evaluate the 12-month follow-up results of intravitreal bevacizumab therapy for macular edema secondary to branch retinal vein occlusion (BRVO) and to identify the pretreatment factors that were associated with an improvement of the final visual outcome.

A total of 50 eyes of 50 patients with macular edema secondary to BRVO received an injection of 1.25 mg/0.05 mL bevacizumab and additional injections were given when recurrence of macular edema occurred or the treatment was not effective. Best-corrected visual acuity and foveal thickness were measured and stepwise multiple regression analyses were performed.

It was reported that the mean logarithm of the minimum angle of resolution visual acuity improved significantly from 0.53 to 0.26, and the mean foveal thickness significantly from 523 to 305 µm during the 12-month follow-up period. The mean number of injections was 2.0 (range, 1-4) and stepwise multiple regression analyses showed that younger patients had both better visual acuity at 12 months and greater improvement of visual acuity during 12 months. Furthermore, better pretreatment visual acuity was associated with better visual acuity at 12 months but with less improvement of the visual acuity.

Intravitreal bevacizumab therapy can be a long-term effective treatment for macular edema secondary to BRVO, it was concluded.

Source: Kondo M, Kondo N, Ito Y, et al. Intravitreal injection of bevacizumab for macular edema secondary to branch retinal vein occlusion: results after 12 months and multiple regression analysis. Retina 2009; 29(9):1242-1248.

Retinal Endothelial Cell Apoptosis and Recruitment of Endothelial Progenitor Cells

To determine how the presence of apoptotic bodies at sites of endothelial damage may influence participation of endothelial progenitor cells (EPCs) in retinal microvascular repair, the authors of this study created microlesions of apoptotic cell death in monolayers of retinal microvascular endothelial cells (RMECs) by using the photodynamic drug verteporfin. They studied the adhesion of early-EPCs to these lesions before detachment of the apoptotic cells or after their removal from the wound site and fed the apoptotic bodies to normal RMECs. They then analyzed mRNA levels for adhesion molecules.

The authors noted that endothelial lesions where apoptotic bodies were left attached at the wound site showed a fivefold enhancement in EPC recruitment (p<0.05) compared with lesions where the apoptotic cells had been removed. In intact RMEC monolayers exposed to apoptotic bodies, expression of ICAM, VCAM and E-selection was upregulated by 5- to 15-fold (p<0.05-0.001). EPCs showed a characteristic chemotactic response (p<0.05) to conditioned medium obtained from apoptotic bodies, whereas analysis of the medium showed significantly increased levels of VEGF, IL-8, IL-6 and TNF- when compared to control medium; SDF-1 remained unchanged.

The data indicate that apoptotic bodies derived from retinal capillary endothelium mediate release of proangiogenic cytokines and chemokines and induce adhesion molecule expression in a manner that facilitates EPC recruitment.

Source: Bhatwadekar AD, Glenn JV, Curtis TM, et al. Retinal endothelial cell apoptosis stimulates recruitment of endothelial progenitor cells. Invest Ophthalmol Vis Sci 2009;50(10):4967-4973.

Affect of Intravitreal Ranibizumab Injection on DME

Scientists administered an intravitreal injection of ranibizumab (0.05 mL/0.5 mg) to 20 consecutive patients with diabetic macular edema (DME) to examine the short-term fluctuation of DME after one injection.

They assessed best-corrected visual acuity (BCVA), fundus biomicroscopy, MP-1 fundus-related perimetry using follow-up strategy (pattern macula 8° 0 dB with threshold strategy 4-2) and performed optical coherence tomography and central macular thickness (CMT) at baseline and 1 hour, 24 hours, 14 days, 28 days and 56 days after intravitreal injection of ranibizumab.

Included for analysis were a total of 18 eyes of 18 patients (9 male, 9 female; mean age, 62.28 ± 8.0 years; range, 48-75 years) who completed the 56-day follow up. The scientists found intravitreal ranibizumab to produce significant improvements in mean BCVA and MP-1 sensitivity, as well as reduction in mean CMT, after one injection. They noted that this anatomical and functional improvement, which compared with baseline, was evident as soon as the 1-hour follow up (mean CMT reduction: t=1.7899, p=0.045; mean MP-1 sensitivity improvement: t=-1.9891, p=0.0315) and lasted until the 56-day follow up (mean BCVA improvement: t=2.26, p<0.05; mean CMT reduction: t=3.61, p<0.05; MP-1 sensitivity improvement: t=-5.21, p<0.05).

The scientists concluded that these short-term observations give insights into the physiopathology of DME treated with an intravitreal ranibizumab injection.

Source: Querques G, Bux AV, Martinelli D, et al. Short-term fluctuation of diabetic macular edema after intravitreal ranibizumab injection. Retina 2009; 29(9):1274-1281.

Foveal Photoreceptor Status and Visual Acuity Following Resolution of DME

Researchers in Japan retrospectively investigated the relationship between the appearance of IS/OS line on OCT images and visual acuity after resolution of DME by vitrectomy to evaluate the correlation between photoreceptor layer status following resolution of diabetic macular edema (DME) by pars plana vitrectomy (PPV) and final visual acuity (VA). They found that postoperative visual acuity of eyes with complete IS/OS after resolution of DME was significantly better than that without complete IS/OS, though macular edema was completely resolved in both groups.

The study researchers retrospectively studied a series of 69 eyes from 58 patients with DME who were treated with PPV. (Of the 69 eyes, 37 that were examined by optical coherence tomography [OCT] for at least 6 months and that showed a final macular thickness of <250µm were included in this study.) Additionally, they assessed the integrity of the photoreceptor inner and outer segments (IS/OS) line in the fovea, using OCT in relation to their VA and other characteristics.

According to the researchers, there were no differences in initial VA or in foveal thickness between eyes with or without complete IS/OS at final observation; however, final VA without complete IS/OS was significantly poorer (p=0.004). They noted that VA had improved by more than 2 lines in eight of 10 eyes with complete IS/OS and in 10 of 27 eyes without complete IS/OS; the groups differed significantly with regard to this percentage (p=0.03).

These researchers determined that the postoperative photoreceptor status of the fovea is closely related to the final VA after resolution of DME by PPV.

Source: Sakamoto A, Nishijima K, Kita M, et al. Association between foveal photoreceptor status and visual acuity after resolution of diabetic macular edema by pars plana vitrectomy. Graefes Arch Clin Exp Ophthalmol 2009;247(10):1325-1330.

Intravitreal Triamcinolone Acetonide for DME

The purpose of this prospective, double-masked, randomized clinical trial was to report the 5-year outcomes from a clinical trial of intravitreal triamcinolone acetonide (IVTA) in eyes with diabetic macular edema (DME) and impaired vision despite previous laser treatment.

A total of 69 eyes (41 patients) were entered into the study, with 34 eyes initially receiving active treatment and 35 eyes receiving placebo. After completing the 2-year visit, all eyes, including those initially randomized to receive placebo, received IVTA according to prospectively defined guidelines. Five-year data were available for 44 of 67 eyes (66%) and for the 23 eyes with missing five-year data, of which 13 received placebo and 10 received IVTA, the last observation was carried forward. Intravitreal injection of 0.1 ml of 40 mg/ml triamcinolone acetonide with adjunctive laser therapy where appropriate was used as intervention. Main outcome measures were improvement of best-corrected logarithm of the minimum angle of resolution visual acuity by ≥5 letters after 5 years compared with baseline and 2 years, and incidence of adverse events. Change in central macular thickness was the secondary outcome.

Improvement of ≥5 letters after 5 years was found in 14 of 33 eyes (42%) initially treated with IVTA compared with 11 of 34 eyes (32%) initially treated with placebo (zGEE=0.81, p=0.4). It was reported that foveal thickness decreased by 30 µm (95% confidence interval, -47 to 107 µm) less in the initial-IVTA group than in the initial-placebo group at 5 years (zGEE=0.76, p=0.45); 5 of 11 eyes (45%) from the initial-IVTA group that were phakic at commencement of the third year required cataract surgery. A similar number of eyes from each group required ongoing treatment from the third year onward with both laser and IVTA, indicating that IVTA treatment for 2 years does not lead to reduction in the risk of recurrent edema.

It was concluded that the majority of eyes that initially improved with IVTA maintained their gain after 5 years. No new safety concerns were identified. IVTA treatment may be considered in carefully selected cases of impaired vision caused by advanced DME that are unresponsive to other interventions.

Source: Gillies MC, Simpson JM, Gaston C, et al. Five-year results of a randomized trial with open-label extension of triamcinolone acetonide for refractory diabetic macular edema. Ophthalmol 2009;116(11):2182-2187.

Six-Month Results of Ranibizumab Treatment for DME

To compare ranibizumab with focal/grid laser or a combination of both in diabetic macular edema (DME), investigators conducted this prospective, randomized, interventional, multi-center clinical trial with 126 patients with DME.

They randomized subjects 1:1:1 to receive 0.5 mg of ranibizumab at baseline and months 1, 3 and 5 (group 1, 42 patients), focal/grid laser photocoagulation at baseline and month 3 if needed (group 2, 42 patients) or a combination of 0.5 mg of ranibizumab and focal/grid laser at baseline and month 3 (group 3, 42 patients). The primary end point was the change from baseline in best-corrected visual acuity (BCVA) at month 6.

The investigators noted that at month 6, the mean gain in BCVA was significantly greater in group 1 ((+7.24 letters, p=0.01, analysis of variance) compared with group 2 (–0.43 letters) and group 3 (+3.80 letters) was not statistically different from groups 1 or 2. Moreover, for patients with data available at 6 months, improvement of 3 lines or more occurred in 8 of 37 (22%) in group 1 compared with 0 of 38 (0%) in group 2 (p=0.002, Fisher exact test) and 3 of 40 (8%) in group 3. Excess foveal thickness was reduced by 50%, 33% and 45% in groups 1, 2 and 3, respectively.

The study investigators determined that during a span of 6 months, ranibizumab injections by the current protocol had a significantly better visual outcome than focal/grid laser treatment in patients with DME.

Source: Nguyen QD, Shah SM, Heier JS, et al. Primary end point (six months) results of the Ranibizumab for Edema of the mAcula in Diabetes (READ-2) study. Ophthalmol 2009;116(11):2175-2181.

Safety and Efficacy of Topical Bevacizumab for CNV

The authors of this German study evaluated the short- and long-term in vivo safety and efficacy of topical bevacizumab application for treatment of corneal neovascularization (CNV) secondary to a variety of corneal diseases.

A total of 30 eyes of 27 patients with progressive CNV (not responding to conventional anti-inflammatory treatment) due to different underlying corneal diseases received topical bevacizumab (Avastin) eye drops (5 mg/ml bevacizumab) for 0.5-12 months (five times/day on average). The authors performed a routine Snellen visual acuity assessment at each visit, followed by ophthalmic examination including fluorescein staining. They also assessed changes of CNV and vessel diameter using morphometry of standardized digital corneal photographs.

The study authors reported that five patients (five eyes) developed new corneal epithelial defects during topical bevacizumab treatment and in 22 patients, no new epithelial defects were observed. Moreover, none of the 27 patients complained about any drug-related ocular or systemic adverse events during follow up. The authors observed no allergic reactions and were able to assess corneal photographs of 21 eyes (19 patients). They noted that the mean reduction in vascularized area during treatment was 61% and that the mean reduction in vessel diameter under topical Avastin therapy was 24%.

Off-label topical bevacizumab therapy against CNV secondary to different corneal diseases was generally well tolerated for up to 12 months, the authors determined. Additionally, Avastin eye drops inhibit CNV and lead to a reduction of the vessel diameter. The results of this study suggest that off-label use of Avastin eye drops is a relatively safe and well-tolerated option for the treatment of CNV. The authors advise that care be taken in patients with epithelial defects and neurotrophic keratopathy.

Source: Koenig Y, Bock F, Horn F, et al. Short- and long-term safety profile and efficacy of topical bevacizumab (Avastin) eye drops against corneal neovascularization. Graefes Arch Clin Exp Ophthalmol 2009;247(10):1375-1382.