Objective To describe effects of ranibizumab and bevacizumab when administered monthly or as needed for two years and to describe the impact of switching to as-needed treatment after a year of monthly treatment. Design Multicenter, randomized clinical trial. Participants Patients (N=1107) who were followed during Year 2 among 1185 patients with neovascular age-related macular degeneration (AMD) who were enrolled in the clinical trial. Interventions At enrollment, patients were assigned to four treatment groups defined by drug (ranibizumab or bevacizumab) and dosing regimen (monthly or as needed). At one year, patients initially assigned to monthly treatment were randomly reassigned to monthly or as needed treatment, without changing the drug assignment. Main Outcome Measure Mean change in visual acuity. Results Among patients following the same regimen for two years, mean gain in visual acuity was similar for both drugs (bevacizumab-ranibizumab difference: −1.4 letters; 95% confidence interval (CI): [−3.7, 0.8]; p=0.21). Mean gain was greater for monthly than for as-needed treatment (difference: −2.4 letters; CI: [−4.8, −0.1]; p=0.046). The proportion without fluid ranged from 13.9% in the bevacizumab-as-needed group to 45.5% in the ranibizumab monthly group (drug p=0.0003; regimen p<0.0001). Switching from monthly to as-needed treatment resulted in greater mean decrease in vision during year 2 (−2.2 letters, p=0.03) and a lower proportion without fluid (−19%, p<0.0001). Rates of death and arteriothrombotic events were similar for both drugs (p>0.60). The proportion of patients with ≥1 systemic serious adverse events was higher with bevacizumab than ranibizumab (39.9% vs. 31.7%; adjusted risk ratio 1.30; CI [1.07, 1.57]; p=0.009). The majority of the excess events have not been associated previously with systemic therapy targeting vascular endothelial growth factor (VEGF). Conclusions Ranibizumab and bevacizumab had similar effects on visual acuity over a two-year period. Treatment as needed resulted in less gain in visual acuity, whether instituted at enrollment or after one year of monthly treatment. There were no differences between drugs in rates of death or arteriothrombotic events. The interpretation of the persistence of higher rates of serious adverse events with bevacizumab is uncertain because of the lack of specificity to conditions associated with inhibition of VEGF.

Purpose To describe risk factors for geographic atrophy (GA) in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT). Design Cohort within a randomized clinical trial. Participants We analyzed 1024 CATT patients with no GA visible on color fundus photographs (CFPs) and/or fluorescein angiograms (FAs) at enrollment. Methods Eyes were assigned to ranibizumab (0.5 mg) or bevacizumab (1.25 mg) treatment and to a 2-year monthly or pro re nata (PRN) injection regimen, or monthly injections for 1 year and PRN for 1 year. Demographic, genetic, and baseline ocular characteristics and lesion features of CFP/FA and optical coherence tomography (OCT) were evaluated as risk factors for GA through 2 years of follow-up. Time-dependent Cox proportional hazard models were used to estimate adjusted hazard ratios (aHRs). Main Outcome Measures Development of GA. Results By 2 years, GA developed in 187 of 1024 patients (18.3%). Baseline risk factors for GA development included baseline visual acuity (VA) ≤20/200 (aHR, 2.65; 95% confidence interval [CI], 1.43–4.93), retinal angiomatous proliferation (RAP; aHR, 1.69; 95% CI, 1.16–2.47), GA in the fellow eye (aHR, 2.07; 95% CI, 1.40–3.08), and intraretinal fluid at the foveal center (aHR, 2.10; 95% CI, 1.34–3.31). Baseline factors associated with lower risk for GA development included blocked fluorescence (aHR, 0.49; 95% CI, 0.29–0.82), OCT measurements of subretinal fluid thickness of >25 μ (aHR, 0.52; 95% CI, 0.35–0.78), subretinal tissue complex thickness of >275 compared with ≤75 μ (aHR, 0.31; 95% CI, 0.19–0.50), and vitreomacular attachment (aHR, 0.55; 95% CI, 0.31–0.97). Ranibizumab compared with bevacizumab had a higher risk (aHR, 1.43; 95% CI, 1.06–1.93), and monthly dosing had a higher risk (aHR, 1.59; 95% CI, 1.17–2.16) than PRN dosing. There were no strong associations between development of GA and the presence of risk alleles for CFH, ARMS 2, HTRA1, C3, or TLR3. Conclusions Approximately one fifth of CATT patients developed GA within 2 years of treatment. Independent baseline risk factors included poor VA, RAP, foveal intraretinal fluid, monthly dosing, and treatment with ranibizumab. Anti-vascular endothelial growth factor therapy may have a role in the development of GA.

Purpose To describe outcomes 5 years after initiation of treatment with bevacizumab or ranibizumab for neovascular age-related macular degeneration (AMD). Design Cohort study.. Participants Patients enrolled in the Comparison of AMD Treatments Trials (CATT). Methods Patients were randomly assigned to ranibizumab or bevacizumab and to 1 of 3 dosing regimens. After 2 years, patients were released from the clinical trial protocol. At approximately 5 years, patients were recalled for examination. Main Outcome Measures Visual acuity (VA) and morphologic retinal features. Results VA was obtained for 647 (71%) of 914 living patients with average follow-up time 5.5 years. The mean number of examinations for AMD care after the clinical trial ended was 25.3, and the mean number of treatments in the study eye was 15.4. Most (60%) patients were treated ≥1 times with a drug other than their randomly assigned drug. At the 5-year visit, 50% of study eyes had VA 20/40 or better and 20% had VA 20/200 or worse. Mean change in VA was −3 letters from baseline and −11 letters from 2 years. Among 467 eyes with fluorescein angiography, mean total lesion area was 12.9 mm2, a mean of 4.8 mm2 larger than at 2 years. Geographic atrophy was present in 213 (41%) of 515 gradable eyes and was subfoveal in 85 (17%). Among 555 eyes with spectral domain optical coherence tomography, 83% had fluid (61% intraretinal, 38% subretinal, and 36% sub-retinal pigment epithelium). Mean foveal total thickness was 278 μm; a decrease of 182 μm from baseline and 20 μm from 2 years. An abnormally thin retina at the foveal center (<120 μm) was present in 36%. Between 2 and 5 years, the group originally assigned to ranibizumab for 2 years lost more VA than the bevacizumab group (−4 letters; p=0.008). Otherwise, there were no statistically significant differences in VA or morphological outcomes between drug or regimen groups. Conclusion Vision gains during the first 2 years of the trial were not maintained at 5 years. However, 50% of eyes had VA 20/40 or better, confirming anti-VEGF therapy as a major long-term therapeutic advance for neovascular AMD.

for Quality Eye Care without any external financial support. Authors and reviewers of the guidelines are volunteers and do not receive any financial compensation for their contributions to the documents. The guidelines are externally reviewed by experts and stakeholders before publication.

Objective-Cross-sectional studies of optical coherence tomography (OCT) show that retinal nerve fiber layer (RNFL) thickness is reduced in multiple sclerosis (MS) and correlates with visual function. We determined how longitudinal changes in RNFL thickness relate to visual loss. We also examined patterns of RNFL thinning over time in MS eyes with and without a prior history of acute optic neuritis (ON).Methods-Patients underwent OCT measurement of RNFL thickness at baseline and at 6-month intervals during a mean follow-up of 18 months at three centers. Low-contrast letter acuity (2.5%, 1.25% contrast) and visual acuity (VA) were assessed.Results-Among 299 patients (593 eyes) with ≥6 months follow-up, eyes with visual loss showed greater RNFL thinning compared to eyes with stable vision (low-contrast acuity, 2.5%: p<0.001; VA: p=0.005). RNFL thinning increased over time, with average losses of 2.9 μm at 2-3 years and 6.1 μm at 3-4.5 years (p<0.001 vs. 0.5-1-year follow-up interval). These patterns were observed for eyes with or without prior history of ON. Proportions of eyes with RNFL loss greater than test-retest variability (≥6.6 μm) increased from 11% at 0-1 year to 44% at 3-4.5 years (p<0.001).Interpretation-Progressive RNFL thinning occurs as a function of time in some patients with MS, even in the absence of ON, and is associated with clinically significant visual loss. These findings are consistent with sub-clinical axonal loss in the anterior visual pathway in MS and support the use of OCT and low-contrast acuity as methods to evaluate the effectiveness of putative neuroprotection protocols.Address all correspondence to: Dr. Laura J. Balcer, Department of Neurology, 3 E. Gates, 3400 Spruce Street, Philadelphia, PA 19104, 215-349-8072, Fax 215-349-5579, lbalcer@mail.med.upenn.edu. NIH Public Access Author ManuscriptAnn Neurol. Author manuscript; available in PMC 2011 June 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptVisual dysfunction is a common cause of disability and reduced quality of life in multiple sclerosis (MS). 1 The anterior visual pathway is a frequent site for inflammation and demyelination, and axonal degeneration is likely to be a final common pathway to permanent visual loss. [2][3][4][5] Recognized by MS experts as a critical dimension for outcomes assessment, 6 vision has been an important area of investigation. The findings of many studies have supported low-contrast letter acuity as a candidate clinical trial outcome measure. It can capture subtle visual impairment, treatment effects, MRI lesion burden, prolonged visual evoked potential latencies, and quality of life. 1,[7][8][9][10][11][12][13] Many ongoing MS trials have incorporated low-contrast acuity as a tertiary outcome.The emergence of optical coherence tomography (OCT) in MS has brought the anterior visual pathway to the forefront as a model for measuring therapeutic efficacy, particularly for trials involving neuroprotection. 14-32 A reliable marker for axonal loss in MS, 24 retina...