Juan E. Grunwald

Ranibizumab and bevacizumab for neovascular age-related macular degeneration.

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 noninferiority 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.).

Ranibizumab and Bevacizumab for Treatment of Neovascular Age-related Macular Degeneration: Two-Year Results

OBJECTIVE To describe effects of ranibizumab and bevacizumab when administered monthly or as needed for 2 years and to describe the impact of switching to as-needed treatment after 1 year of monthly treatment. DESIGN Multicenter, randomized clinical trial. PARTICIPANTS Patients (n = 1107) who were followed up during year 2 among 1185 patients with neovascular age-related macular degeneration who were enrolled in the clinical trial. INTERVENTIONS At enrollment, patients were assigned to 4 treatment groups defined by drug (ranibizumab or bevacizumab) and dosing regimen (monthly or as needed). At 1 year, patients initially assigned to monthly treatment were reassigned randomly to monthly or as-needed treatment, without changing the drug assignment. MAIN OUTCOME MEASURES Mean change in visual acuity. RESULTS Among patients following the same regimen for 2 years, mean gain in visual acuity was similar for both drugs (bevacizumab-ranibizumab difference, -1.4 letters; 95% confidence interval [CI], -3.7 to 0.8; P = 0.21). Mean gain was greater for monthly than for as-needed treatment (difference, -2.4 letters; 95% CI, -4.8 to -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 or more systemic serious adverse events was higher with bevacizumab than ranibizumab (39.9% vs. 31.7%; adjusted risk ratio, 1.30; 95% CI, 1.07-1.57; P = 0.009). Most 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 2-year period. Treatment as needed resulted in less gain in visual acuity, whether instituted at enrollment or after 1 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.

Retinal Autoregulation in Open-angle Glaucoma

The macular blood flow response to an induced change in intraocular pressure (autoregulation) was studied using the blue field entopic phenomenon in 11 open angle glaucoma patients, eight glaucoma suspects and 13 normal volunteers. A suction cup was used to raise the intraocular pressure (IOP) above its resting state (IOPrest). IOPmax, the highest acutely increased IOP for which blood flow can be maintained constant by autoregulation, was 24.9 +/- 1.5 mmHg (+/- 1 SD) in the glaucoma patients, 30.8 +/- 4.6 mmHg in the glaucoma suspects and 29.9 +/- 3.6 mmHg in the normal subjects. The values for IOPmax - IOPrest were 3.7 +/- 4.3 mmHg, 4.7 +/- 3.3 mmHg, and 14.3 +/- 3.1 mmHg, respectively. After the release of the suction cup, a hyperemic response was observed by 16 of 17 normal eyes, 10 of 14 glaucoma suspect eyes and only 9 of 19 glaucomatous eyes. These results suggest an abnormal autoregulation of macular retinal blood flow in open-angle glaucoma.

Fibroblast Growth Factor-23 and Cardiovascular Events in CKD

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], 44±15 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], 1.45 per doubling [95% confidence interval (CI), 1.28 to 1.65]; HR for highest versus lowest quartile, 2.98 [95% CI, 1.97 to 4.52]) and atherosclerotic events (HR per doubling, 1.24 [95% CI, 1.09 to 1.40]; HR for highest versus lowest quartile, 1.76 [95% CI, 1.20 to 2.59]). 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.

Altered Retinal Vascular Response to 100% Oxygen Breathing in Diabetes Mellitus

The effect of 100% oxygen breathing on retinal blood flow was investigated using laser Doppler velocimetry in 19 normal eyes, and in 41 eyes of insulin treated diabetic patients. Of the diabetic eyes studied, nine had no retinopathy, 18 had background diabetic retinopathy, seven had proliferative diabetic retinopathy, and seven had proliferative diabetic retinopathy that had been previously treated by argon panretinal photocoagulation. Five minutes of 100% oxygen breathing produced an average decrease in blood flow of 61% (SD = 8) in normal eyes, 53% (SD = 10) in NR eyes, 38% (SD = 13) in background diabetic retinopathy eyes, 24% (SD = 18) in proliferative diabetic retinopathy eyes and 54% (SD = 8) in panretinal photocoagulation eyes. In six eyes with proliferative retinopathy measured before and after panretinal photocoagulation, a significant increase in vascular response to O2 was observed following photocoagulation (Wilcoxon signed rank test, P less than 0.05).

Retinal vascular autoregulation in diabetes mellitus.

The blue field entoptic technique was used to study autoregulation of the macular retinal circulation in response to acute alterations of intraocular pressure in 71 diabetic eyes and 30 normals matched for age, systemic blood pressure, and ophthalmic artery diastolic pressure. IOPmax, the maximal intraocular pressure at which flow is maintained normal by autoregulation, was normal in eyes with no retinopathy (30 +/- 3.2 mm Hg) but decreased with progression of retinopathy, approaching the resting intraocular pressure in eyes with proliferative retinopathy. The hyperemia observed by normals to an acute reduction of intraocular pressure was not observed frequently in the diabetics with no retinopathy. The frequency of observation of the hyperemia decreased with progression of retinopathy and was uniformly absent in eyes with proliferative retinopathy. A group of eyes with minimal microangiopathy was found to have an abnormal IOPmax and no hyperemic response. The prognostic significance of these parameters remains to be established.

Baseline Predictors for One-Year Visual Outcomes with Ranibizumab or Bevacizumab for Neovascular Age-related Macular Degeneration

OBJECTIVE To determine the baseline predictors of visual acuity (VA) outcomes 1 year after treatment with ranibizumab or bevacizumab for neovascular age-related macular degeneration (AMD). DESIGN Cohort study within the Comparison of Age-related Macular Degeneration Treatments Trials (CATT). PARTICIPANTS A total of 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 a monthly or as-needed schedule. Masked readers evaluated fundus morphology and features on optical coherence tomography (OCT). Visual acuity was measured using electronic VA testing. Independent predictors were identified using regression techniques. MAIN OUTCOME MEASURES The VA score, VA score change from baseline, and ≥3-line gain at 1 year. RESULTS At 1 year, the mean VA score was 68 letters, mean improvement from baseline was 7 letters, and 28% of participants gained ≥3 lines. 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 second quartile (325-425 μm) had the best VA (P=0.01) and were most likely to gain ≥3 lines (P=0.004). Predictors did not vary by treatment group. CONCLUSIONS 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 optical coherence tomography were independently associated with less improvement in VA at 1 year. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Retinal haemodynamics in patients with early diabetes mellitus.

AIMS/BACKGROUND: The retinal circulation was investigated in a group of 19 patients with insulin dependent diabetes mellitus with less than 4 years of disease duration and no evidence of diabetic retinopathy. Results of these patients were compared with those of 16 age-matched normal controls. METHODS: Venous diameter (D) was measured from monochromatic fundus photographs. Maximum erythrocyte velocity (Vmax) was assessed by bidirectional laser Doppler velocimetry in the major retinal veins of one eye of each subject. Total volumetric blood flow rate (QT) was calculated by adding the flow rates of the major retinal veins. RESULTS: Average QT was 12% larger than normal in diabetic patients (one tailed, non-paired Students t test, p < 0.05). A statistically significant correlation was observed between QT and disease duration (r = 0.35, p < 0.04). Patients with longer disease duration tended to have somewhat larger QT. The average retinal vascular regulatory responses to hyperoxia were not significantly different from normal in diabetic patients. In these patients, however, higher blood glucose levels were associated with decreased regulatory responses to hyperoxia. CONCLUSIONS: Patients with diabetes mellitus of relatively short duration have mildly increased QT, suggesting that increased blood flow may play an early role in the development of diabetic retinal microangiopathy.

Use of the retinal vessel analyzer in ocular blood flow research

Acta Ophthalmol. 2010: 88: 717–722

Fundus camera based retinal LDV

A new bidirectional laser Doppler velocimeter (LDV) is described for absolute measurement of the speed of red blood cells flowing in individual retinal vessels. The basic component of the instrument is a standard retinal camera that eliminates the need for a contact lens. The laser beam is delivered to the eye through the fundus illumination optical system of the camera. Target fixation is done with the eye under examination. The measurements are independent from the ocular refraction; only the axial length of the eye need be determined. The instrument markedly simplifies the technique of retinal blood flow measurement.