Stuart L. Fine

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.

Photocoagulation Treatment of Proliferative Diabetic Retinopathy: The Second Report of Diabetic Retinopathy Study Findings

Data from the Diabetic Retinopathy Study (DRS) show that photocoagulad inhibited the progression of retinopathy. These beneficial effects were noted to some degree in all those stages of diabetic retinopathy which were included in the Study. Some deleterious effects of treatment were also found, including losses of visual acuity and constriction of peripheral visual field. The risk of these harmful effects was considered acceptable in eyes with retinopathy in the moderate or severe retinopathy in the moderate or severe proliferative stage when the risk of severe visual loss without treatment was great. In early proliferative or severe nonproliferative retinopathy, when the risk of severe visual loss without treatment was less, the risks of harmful treatment effects assumed greater importance. In these earlier stages, DRS findings have not led to a clear choice between prompt treatment and deferral of treatment unless and until progression to a more severe stage occurs.

Natural Course of Choroidal Neovascular Membranes Within the Foveal Avascular Zone in Senile Macular Degeneration

We divided 96 eyes (93 patients) with senile macular degeneration and choroidal neovascular membranes into two groups--those with juxtafoveal membranes (1 to 250 mu from the center of the foveal avascular zone) and those with subfoveal membranes (0 mu from the center of the zone). After an average follow-up period of 21 months, one of 38 eyes in the juxtafoveal group (3%) had improved two or more lines on the Snellen chart, three eyes (8%) had remained the same, and 34 eyes (89%) had lost two or more lines on the Snellen chart. Although 35 of the 38 eyes (92%) had had initial visual acuities of 6/30 (20/100) or better, 27 eyes (71%) had become legally blind. Of the 58 eyes in the subfoveal group, 18 (31%) had remained the same or improved and 40 (69%) had lost two or more lines on the Snellen chart; 41 (70%) had final visual acuities of 6/60 (20/20) or worse. Of the 26 eyes in the subfoveal group that had had initial visual acuities of 6/60 (20/100) or better (45%). four (15%) had stayed the same and 22 (85%) had lost two or more lines on the Snellen chart. Fourteen of the 26 eyes (54%) had final visual acuities of 6/60 (20/200) or worse. Exudative maculopathy developed in the second eye in 13% of patients who initially had unilateral choroidal neovascularization after 12 months, in 22% after 24 months, and in 29% after 36 months, using life table analysis.

Clinicopathologic correlation of drusen and retinal pigment epithelial abnormalities in age-related macular degeneration.

Background: Clinicopathologic studies of eyes lead to a better understanding of the nature of the ophthalmoscopic and fluorescein angiographic features of drusen. A study was conducted to provide clinicopathologic correlation of drusen and present a classification of drusen based on clinical and histopathologic features. Methods: The macular areas of three eyes from two patients were serially sectioned and studied, and features were depicted in a two-dimensional map and compared with clinical findings. Results: All three tyes had large drusen (>63 µm) with soft morphologic characteristics (poorly demarcated borders) documented on fundus photographs. In both eyes from one patient, these large drusen corresponded to areas of focal retinal pigment epithelium hypopigmentation overlying Bruchs membrane, which was diffusely thickened throughout the macula. Similar findings were noted in another eye from a second patient, and additionally, where there was relatively marked fluorescein staining of large drusen on the late phase of an angiogram, the pathologic correlation demonstrated detachment of the thickened inner aspect of Bruchs membrane from the remainder of Bruchs membrane. Focal hyperpigmentation corresponded to areas of hypertrophy of the retinal pigment epithelium and to clusters of pigmented cells in the subretinal space and outer nuclear area. Conclusion: Diffuse thickening of the inner aspect of Bruchs membrane is associated with retinal pigment epithelial hypopigmentation, focal atrophy, and soft (large) drusen formation.

Prognosis of Patients with Bilateral Macular Drusen

Of 71 patients with only bilateral macular drusen, 8 eyes in 7 patients (9.9%) developed exudative maculopathy over an average follow-up of 4.3 years (14.5% cumulative risk). Severe visual loss due to exudative maculopathy occurred in 7 eyes of 6 patients (8.5%) for a 5-year cumulative risk of 12.7%. Features of the drusen were analyzed, but only the association with focal hyperpigmentation (P less than 0.001) and more than minimal drusen confluence (P less than 0.05) were statistically significant. Older patients had more severe drusen. Photostress test delay did not correlate with visual acuity, age, or severity of drusen.

Frequency of Adverse Systemic Reactions after Fluorescein Angiography: Results of a Prospective Study

Intravenous fluorescein angiography is a commonly performed and extraordinarily valuable diagnostic procedure. The frequency of adverse reactions after angiography has varied considerably in previous reports. In a prospective study of 2789 angiographic procedures in 2025 patients, the authors found that the percentage of adverse reactions depended strongly on the patients angiographic history. Overall, adverse reactions followed 4.8% of the angiographic procedures. These reactions included nausea (2.9%), vomiting (1.2%), flushing/itching/hives (0.5%), and other reactions (dyspnea, syncope, excessive sneezing) (0.2%). No cases of anaphylaxis, myocardial infarction, pulmonary edema, or seizures occurred. The percentage of reactions was 1.8% for patients who had had previous angiography without ever having had an adverse reaction. In contrast, the percentage of reactions was 48.6% for patients who had had an adverse reaction to angiography previously.

Clinical Features of Idiopathic Macular Cysts and Holes

Of 52 patients (39 women and 13 men; mean age, 65 years) with idiopathic macular cysts or holes, 17 had bilateral involvement. During a mean follow-up period of 28 months, 50% of the macular cysts progressed to holes. Eight of nine eyes with cysts and visual acuities of 6/15 (20/50) or worse at the initial examination developed holes. No holes developed in eyes that had not had cysts at the initial examination. This demonstrated the importance of examining the fellow eye when making a prognosis. Posterior vitreous detachment was present in all the eyes with macular holes and absent in all the eyes with macular cysts at the initial examination. Whenever a cyst progressed to a hole, posterior vitreous detachment also developed. Twenty-five patients had systemic hypertension, 31 had undergone a hysterectomy, taken systemic estrogen, or both, three had adult-onset diabetes mellitus, and 12 smoked cigarettes.

Vision-threatening Complications of Surgery for Full-thickness Macular Holes

OBJECTIVE To study complications of vitrectomy surgery for full-thickness macular holes. DESIGN A multicentered, randomized, controlled clinical trial. PARTICIPANTS Community and university-based ophthalmology clinics. INTERVENTION Standardized macular hole surgery versus observation. MAIN OUTCOME MEASURES Assessment of anatomic and visual outcomes and determination of postoperative complications at 12 months after randomization. RESULTS Posterior segment complications were noted in 39 eyes (41%). The incidence of retinal pigment epithelium (RPE) alteration and retinal detachment (RD) were 33% and 11%, respectively. One RD due to a giant retinal tear resulted in a visual acuity of light perception. Other complications included a reopening of the macular hole in 2 eyes (2%), cystoid macular edema in 1 eye (1%), a choroidal neovascular membrane in 1 eye (1%) and endophthalmitis in 1 eye (1%). Eyes with complications had significantly worse visual acuity outcomes as determined by the Early Treatment Diabetic Retinopathy Study, Word Reading, and Potential Acuity Meter charts (P < 0.01 for all comparisons). Eyes with macular holes greater than 475 microns were more than twice as likely to have complications than eyes with holes less than 475 microns (odds ratio [OR] = 2.2, P = 0.07). Before surgery, the stage of the hole was related to postoperative RPE changes (P < 0.0001) and the occurrence of postoperative RD (P = 0.0002). Intraoperative trauma was related to the occurrence of these complications (P < 0.0001 for RPE changes, P = 0.02 for RDs). Epiretinal membrane removal was related to RPE changes (P = 0.02) but not RDs. CONCLUSIONS The RPE alterations and RDs are common after macular hole surgery and result in significantly reduced postoperative visual acuity. The RPE changes may be related to surgical trauma or light toxicity. Further efforts to reduce complications associated with macular hole surgery are indicated.

Choroidal Neovascularization after Laser Photocoagulation for Diabetic Macular Edema

Choroidal neovascular membranes (CNVMs) developed in eight patients after photocoagulation for clinically significant diabetic macular edema (DME). The CNVMs developed in areas where Bruchs membrane was ruptured and were diagnosed 2 weeks to 5 months after treatment. Only six patients had symptoms. The CNVMs were treated in four patients; final visual acuity was poor in all eight patients. This serious complication that follows laser treatment for DME may be related to the use of repeated small-size, short-duration laser or intense laser burns, or both.