ARVO 2011 presents a diverse offering of new research that covers just about all aspects of the retina. Age-related macular degeneration is once again a mainstay topic, involving new and established therapies. Supplements such as lutein and zeaxanthin are explored, as are diagnostic approaches, including a home-monitoring device.
CATT Study Results
Since 2005, when reports began appearing in the literature showing the effectiveness of bevacizumab (Avastin, Genentech) for the treatment of choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD), there has been much debate regarding which anti-VEGF drug should be the treatment of choice: ranibizumab (Lucentis, Genentech), the drug that was specifically engineered for treating CNV, or the much less expensive, off-label drug bevacizumab. Now finally, there is an answer.
Results from the National Eye Institute’s (NEI) Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) suggested that the less expensive drug Avastin was shown to have equal therapeutic efficacy to its more expensive counterpart Lucentis, confirming what retinal specialists had already long believed. The CATT study was important because it provides a scientific basis in the form of a randomized, controlledclinical trial for recommending Avastin over Lucentis.
Findings for VEGF Trap-Eye
Regeneron Pharmaceuticals, Inc. has a vascular endothelial growth factor (VEGF) trap in clinical trials that shows great promise. The company is presenting its Phase III data for AMD and macular edema.
VEGF Trap-Eye (VTE) is an intravitreally administered fusion protein that binds the pro-angiogenic factors VEGF-A and placental growth factor. One key study compared different doses and dosing regimens of VTE with laser photocoagulation in patients with diabetic macular edema (DME).6646
A total of 221 patients were randomized to one of five treatment regimens: VTE 0.5mg every four weeks; 2mg every four weeks; 2mg for three initial monthly doses followed by dosing every eight weeks; 2mg for three initial monthly doses followed by dosing as-needed; or macular laser photocoagulation. Significant gains in best-corrected visual acuity were found at week 24 and maintained or improved for up to week 52 weeks in all VTE groups, including the group receiving 2mg VTE every other month. The researchers concluded that VTE may offer benefits in the treatment of DME.
Another study looked at the efficacy and safety of VTE vs. ranibizumab in patients with choroidal neovascularization (CNV) secondary to AMD.3073 In this study of 1,217 patients in North America, researchers found that 2mg of VTE every month was significantly better than ranibizumab 0.5mg every month. Differences between the other VTE groups and ranibizumab were insignificant. Dosing monthly or every two months with VTE was about as good as monthly ranibizumab. VTE was generally well tolerated and had a generally favorable safety profile. Based on these results, the study found that VTE may provide convenient management of wet AMD with predictable dosing every two months.
A randomized, double-masked, controlled Phase III study evaluated the efficacy and safety of VTE in patients with macular edema secondary to central retinal vein occlusion (CRVO) after 24 weeks of treatment.6643 In this study, 114 patients received six monthly injections of 2mg VTE and 73 patients received control sham injections.
Researchers concluded that monthly dosing with 2mg VTE in patients with macular edema secondary to CRVO resulted in a statistically significant improvement in visual acuity compared to control sham treatment.
Lutein, Zeaxanthin and ARM
Lutein and zeaxanthin potentially may protect against age-related maculopathy (ARM) and associated oxidation via blue light absorption. However, results of relevant epidemiological studies have been inconsistent. One report of 963 elderly French subjects with ARM indicated an association with plasma carotenoids.96/A231
After multivariate adjustment, subjects with high plasma concentration of lutein and combined lutein/zeaxanthin were found to be at higher risk for early ARM. The association with zeaxanthin alone was not statistically significant. Also, the other stages of ARM were not significantly associated with lutein or zeaxanthin.
The current results of the study did not favor a reduced risk for ARM with high plasma levels of lutein and zeaxanthin. The results might be explained by residual confounding, in particular by sunlight exposure, which has yet to be estimated in the same study.
Preferential Hyperacuity Perimetry
Large, randomized trials have demonstrated that better initial visual acuity and smaller lesion size are predictors of better absolute acuity following therapy. Therefore, early detection may afford better patient outcomes. The purpose of one study was to determine whether a home-based preferential hyperacuity perimeter (PHP) could detect early conversion from dry to wet AMD and to assess the stability of patient testing over time.3069
In patients with intermediate AMD, frequent monitoring with the home-based PHP was applied successfully, producing stable test scores over several months. New cases of CNV were detected with high sensitivity and specificity in asymptomatic patients.
PHP is also used to detect and characterize metamorphopsia. One study was designed to evaluate the rate of false positive alerts between clinical visits.3542/A340 This prospective, observational cohort study of patients with intermediate nonexudative AMD was performed using the home-based PHP device. PHP was determined to be a useful tool for monitoring the vision of intermediate AMD patients at home, with a low rate of false positive alerts between clinical visits.
Retinal Vascular Disease
The Ranibizumab for Edema of the Macula in Diabetes (READ2) trial compared ranibizumab injections (group 1) to laser treatment (group 2) and ranibizumab and laser treatment (group 3) for six months.5332
A change in protocol allowing as needed ranibizumab injections every month instead of every two months resulted in a significant reduction in mean foveal thickness and improvement in best-corrected visual acuity in groups 1 and 3. These results suggested that many patients with DME require frequent injections of ranibizumab to optimally control edema and maximize vision.
Nonbioerodible Drug Delivery System
Researchers sought to determine the efficacy and safety of a nonbioerodible drug delivery system that provides a sustained, submicrogram dose of fluocinolone acetonide (FAc) with near zero-order release kinetics.6645 In randomized, phase III, double-masked, sham-controlled, multicenter, parallel-group trials that evaluated FAc intravitreal inserts in 956 patients with DME, the efficacy and safety of two doses (0.2µg/day and 0.5µg/day) were compared with a sham control over 36 months.
The results of the FAME (Fluocinolone Acetonide in Diabetic Macular Edema) program showed that significantly more patients in the 0.2µg/day FAc group experienced ≥ 15-letter vision gain at 24 months than controls (28.7% vs. 16.2%, respectively). Based on these results, the 0.2µg/day FAc (Iluvien, Alimera Sciences) has been submitted for regulatory approval. Iluvien significantly improves visual acuity and anatomical outcomes in DME patients with a low risk of incisional procedures for increased intraocular pressure.
Treating DME with Anti-VEGF
Anti-vascular endothelial growth factor therapy may provide a therapeutic benefit in both anatomic and functional endpoints in DME. RISE and RIDE—two identical, parallel Phase II studies––have endured as the longest sham-controlled trials to date evaluating monthly ranibizumab in DME patients.6647
In RISE, subjects treated monthly with ranibizumab for 24 months experienced early, sustained, and statistically significant improvements in best-corrected visual acuity and OCT, compared to subjects in the sham group. Overall ocular adverse rates of these events were similar to those reported in other studies of laser, ranibizumab and/or triamcinolone in DME.
Steroid Drops for DME
One study looked at the efficacy of topical 1.5% dexamethasone aqueous eye drops prepared by cyclodextrin nanoparticle technology (Dex-Cx) for DME.585/A325 In this pilot study of 16 eyes with chronic DME, topical Dex-Cx eye drops were shown to decrease central macular thickness in DME and improve visual acuity. The efficacy of the eye drops was enhanced in vitrectomized eyes.
Vitrectomy With or After Phaco
One study compared the outcomes of vitrectomy performed in combination with phacoemulsification and intraocular lens implantation to the outcomes of vitrectomy performed in pseudophakic patients.2138/A108 Researchers evaluated macular hole closure rate, visual outcomes and complications involved in 25-, 23- and 20-gauge vitrectomies. In addition, this study of 88 patients aimed to compare visual outcomes and complications of vitrectomies that were done with indocyanine green (ICG) dye assistance as well as procedures done with gas (C3F8 or SF6) tamponade.
Combination surgery appeared to lead to better visual outcomes than sequential surgery in pseudophakic patients. Consecutive surgery in patients with mild cataracts at baseline was as effective as combination surgery. A faster improvement in visual acuity was achieved with 25-gauge vitrectomy than with 20- and 23-gauge vitrectomy. Patients receiving SF6 showed a greater improvement in visual acuity than patients receiving C3F8.
Anti-VEGF for Endophthalmitis
Researchers assessed the rate of clinical and microbiological features of eyes that develop clinically suspected endophthalmitis following intravitreal injections of anti-VEGF agents.5926 The retrospective consecutive case series focused on 58,453 patients in a university-based referral center and three university-owned satellite clinics.
Twelve cases (eleven patients) that were evaluated involved endophthalmitis, allowing researchers to confirm a very low rate of the acute infection after administration of these intravitreal injections. Infection in affected patients, however, was generally associated with poor visual outcomes. The rate of clinically suspected endophthalmitis was 0.023% after bevacizumab and 0.036% after ranibizumab.
Idiopathic Macular Telangiectasia
Type 2 idiopathic macular telangiectasia (MacTel) can cause progressive loss of central vision and marked visual dysfunction in the middle-aged and elderly. Previous studies have shown no benefit from grid laser photocoagulation in the non-proliferative subtype or PDT in the proliferative subtype. Published literature suggests an improvement in visual acuity with intravitreal bevacizumab with type 2 proliferative MacTel. Researchers sought to describe the results of intravitreal ranibizumab therapy in a series of patients with type 2 MacTel.4529/A397
Eight eyes of six patients (mean age: 78.4 years) were involved, including five eyes with proliferative MacTel. Early results indicated that intravitreal ranibizumab therapy was associated with good results in the non-proliferative subtype of MacTel.
Biomarkers for Early AMD?
For clinicians managing neovascular complications of AMD, an effective biomarker is still needed to improve early disease detection, identify progression risk and enable monitoring intervention efficacy.
In a study of 157 participants aged 73±9 years, researchers sought to determine the role of urinary profiles of pro-inflammatory cytokines, Transforming Growth Factor-β1 (TGF-β1), Macrophage Chemoattractant Protein-1 (MCP-1) and C3a-desArg as potential biomarkers for detection and monitoring AMD.4006/A144
Logistic regression analyses, adjusted for age, demonstrated a significant association of elevated urinary TGF-β1 levels and MCP-1 levels with early AMD and also elevated MCP-1 levels with geographic atrophy. There was no correlation between urinary and serum cytokine levels.