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.

BACKGROUND Clinical trials have established the efficacy of ranibizumab for the treatment of neovascular age-related macular degeneration (AMD). In addition, bevacizumab is used off-label to treat AMD, despite the absence of similar supporting data. METHODS In a multicenter, single-blind, noninferiority trial, we randomly assigned 1208 patients with neovascular AMD to receive intravitreal injections of ranibizumab or bevacizumab on either a monthly schedule or as needed with monthly evaluation. The primary outcome was the mean change in visual acuity at 1 year, with a non-inferiority limit of 5 letters on the eye chart. RESULTS Bevacizumab administered monthly was equivalent to ranibizumab administered monthly, with 8.0 and 8.5 letters gained, respectively. Bevacizumab administered as needed was equivalent to ranibizumab as needed, with 5.9 and 6.8 letters gained, respectively. Ranibizumab as needed was equivalent to monthly ranibizumab, although the comparison between bevacizumab as needed and monthly bevacizumab was inconclusive. The mean decrease in central retinal thickness was greater in the ranibizumab-monthly group (196 μm) than in the other groups (152 to 168 μm, P = 0.03 by analysis of variance). Rates of death, myocardial infarction, and stroke were similar for patients receiving either bevacizumab or ranibizumab (P>0.20). The proportion of patients with serious systemic adverse events (primarily hospitalizations) was higher with bevacizumab than with ranibizumab (24.1% vs. 19.0%; risk ratio, 1.29; 95% confidence interval, 1.01 to 1.66), with excess events broadly distributed in disease categories not identified in previous studies as areas of concern. CONCLUSIONS At 1 year, bevacizumab and ranibizumab had equivalent effects on visual acuity when administered according to the same schedule. Ranibizumab given as needed with monthly evaluation had effects on vision that were equivalent to those of ranibizumab administered monthly. Differences in rates of serious adverse events require further study. (Funded by the National Eye Institute; ClinicalTrials.gov number, NCT00593450.)

A classification system and criteria for OCT-defined atrophy in the setting of AMD has been proposed based on an international consensus. This classification is a more complete representation of changes that occur in AMD than can be detected using color fundus photography alone. Longitudinal information is required to validate the implied risk of vision loss associated with these terms. This system will enable such future studies to be undertaken using consistent definitions.

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.

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An elevated level of fibroblast growth factor-23 (FGF-23) is the earliest abnormality of mineral metabolism in CKD. High FGF-23 levels promote left ventricular hypertrophy but not coronary artery calcification. We used survival analysis to determine whether elevated FGF-23 is associated with greater risk of adjudicated congestive heart failure (CHF) and atherosclerotic events (myocardial infarction, stroke, and peripheral vascular disease) in a prospective cohort of 3860 participants with CKD stages 2-4 (baseline estimated GFR [eGFR], 44615 ml/min per 1.73 m 2 ). During a median follow-up of 3.7 years, 360 participants were hospitalized for CHF (27 events/1000 person-years) and 287 had an atherosclerotic event (22 events/1000 person-years). After adjustment for demographic characteristics, kidney function, traditional cardiovascular risk factors, and medications, higher FGF-23 was independently associated with graded risk of CHF (hazard ratio [HR] . Elevated FGF-23 was associated more strongly with CHF than with atherosclerotic events (P=0.02), and uniformly was associated with greater risk of CHF events across subgroups stratified by eGFR, proteinuria, prior heart disease, diabetes, BP control, anemia, sodium intake, income, fat-free mass, left ventricular mass index, and ejection fraction. Thus, higher FGF-23 is independently associated with greater risk of cardiovascular events, particularly CHF, in patients with CKD stages 2-4.

Objective To determine baseline predictors of visual acuity (VA) outcomes at 1 year after treatment with ranibizumab or bevacizumab for neovascular age-related macular degeneration (AMD). Design Cohort study within the Comparison of AMD Treatments Trials. Participants 1105 participants with neovascular AMD, baseline VA 20/25 to 20/320, and VA measured at 1 year. Methods Participants were randomly assigned to ranibizumab or bevacizumab on either a monthly or as-needed schedule. Masked readers evaluated fundus morphology, and features on optical coherence tomography (OCT). VA was measured using electronic visual acuity testing. Independent predictors were identified using regression techniques. Main Outcome Measures VA score, VA score change from baseline, and ≥3-line gain at 1 year. Results At one year, the mean VA score was 68 letters, mean improvement from baseline was 7 letters, and 28% of participants gained ≥3-line. Older age, larger area of choroidal neovascularization (CNV), and elevation of retinal pigment epithelium (RPE) were associated with worse VA (all p<0.005), less gain in VA (all p<0.02) and a lower proportion gaining ≥3-lines (all p<0.04). Better baseline VA was associated with better VA at 1 year, less gain in VA, and a lower proportion gaining ≥3-lines (all p<0.0001). Predominantly or minimally classic lesions were associated with worse VA than occult lesions (66 vs. 69 letters, p=0.0003). Retinal Angiomatous Proliferans (RAP) lesions were associated with more gain in VA (10 vs. 7 letters, p=0.03) and a higher proportion gaining ≥3-lines (odds ratio=1.9, 95% confidence interval: 1.2 – 3.1). Geographic atrophy (GA) was associated with worse VA (64 vs. 68 letters, p=0.02). Eyes with total foveal thickness in the 2nd quartile (325 – 425 microns) had the best visual acuity (p=0.01) and were most likely to gain ≥3 lines (p=0.004). Predictors did not vary by treatment group. Conclusion For all treatment groups, older age, better baseline VA, larger CNV area, predominantly or minimally classic lesion, absence of RAP lesion, presence of GA, greater total fovea thickness and RPE elevation on OCT were independently associated with less improvement in VA at 1 year.