Glenn J. Jaffe

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.

Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel.

PURPOSE To provide recommendations for the use of immunosuppressive drugs in the treatment of patients with ocular inflammatory disorders. PARTICIPANTS A 12-person panel of physicians with expertise in ophthalmologic, pediatric, and rheumatologic disease, in research, and in the use of immunosuppressive drugs in patient care. EVIDENCE Published clinical study results. Recommendations were rated according to the quality and strength of available evidence. PROCESS The panel was convened in September of 1999 and met regularly through May 2000. Subgroups of the panel summarized and presented available information on specific topics to the full panel; recommendations and ratings were determined by group consensus. CONCLUSIONS Although corticosteroids represent one of the mainstays in the management of patients with ocular inflammation, in many patients, the severity of the disease, the presence of corticosteroid side effects, or the requirement for doses of systemic corticosteroids highly likely to result in corticosteroid complications supports the rationale for immunosuppressive drugs (for example, antimetabolites, T-cell inhibitors, and alkylating agents) being used in the management of these patients. Because of the potential for side effects, treatment must be individualized and regular monitoring performed. With careful use of immunosuppressive drugs for treatment of ocular inflammatory disorders, many patients will benefit from them either with better control of the ocular inflammation or with a decrease in corticosteroid side effects.

Fluocinolone acetonide sustained drug delivery device to treat severe uveitis.

PURPOSE Uveitis is often a chronic disease requiring long-term medical therapy. In this report, we describe a pilot safety and efficacy trial of a novel sustained drug delivery system containing fluocinolone acetonide to treat patients with severe uveitis. DESIGN Prospective, noncomparative, interventional case series PARTICIPANTS Patients with severe uveitis. METHODS Sustained drug delivery devices designed to release fluocinolone acetonide for at least 2.5 years were implanted through the pars plana into the vitreous cavity of seven eyes of five patients. All patients had severe uveitis not well controlled with, or intolerant to, repeated periocular corticosteroid injections, systemic corticosteroids, nonsteroidal immunosuppressive agents, or a combination thereof at the time of device implantation. Before device implantation, patients underwent complete evaluation including history, ophthalmologic examination, fluorescein angiography, visual field testing, and electroretinography. After surgery, patients were reexamined at 1 week, 2 weeks, 4 weeks, and at 1- to 3-month intervals. Visual fields, electroretinograms, and fluorescein angiography were repeated at 3- to 6-month intervals. MAIN OUTCOME MEASURES Preoperative and postoperative visual acuity, ocular inflammation, anti-inflammatory medication use, and intraocular pressure. RESULTS Patients had a diagnosis of Behçets syndrome (two eyes), or idiopathic panuveitis (five eyes, including two with necrotizing retinitis, two with progressive chorioretinitis, and one with iridocyclitis and intermediate uveitis). Patients were observed an average of 10 months (range, 5-19 months). All eyes had stabilized or improved visual acuity after device implantation, and four of seven eyes had an improvement of three lines or more. The mean initial visual acuity, measured by Snellen chart, was 20/207, and the mean final visual acuity was 20/57 (P = 0.02). After surgery, at the final visit, no eye had clinically detectable inflammation, and all seven eyes had a marked reduction in systemic, topical, and periocular anti-inflammatory medication use. Four eyes had increased intraocular pressure 6 weeks to 6 months after device implantation. Intraocular pressure has been controlled on topical medications. No patient experienced intraoperative complications. CONCLUSIONS A fluocinolone acetonide sustained drug delivery device is a promising new therapy for the treatment of severe uveitis. Intraocular pressure must be carefully monitored long after device implantation. Based on these data, a randomized study of a larger group of patients is warranted.

Treatment of posterior uveitis with a fluocinolone acetonide implant: three-year clinical trial results.

OBJECTIVES To evaluate the safety and efficacy of 0.59-mg and 2.1-mg fluocinolone acetonide (FA) intravitreous implants in noninfectious posterior uveitis. DESIGN A 3-year, multicenter, randomized, historically controlled trial of the 0.59-mg FA intravitreous implant in 110 patients and the 2.1-mg FA intravitreous implant in 168 patients. MAIN OUTCOME MEASURES Recurrence rate, vision, and complications. RESULTS Uveitis recurrence was reduced in implanted eyes from 62% (during the 1-year preimplantation period) to 4%, 10%, and 20% during the 1-, 2-, and 3-year postimplantation periods, respectively, for the 0.59-mg dose group (P < .01) and from 58% to 7%, 17%, and 41%, respectively, for the 2.1-mg dose group (P < .01). More implanted eyes than nonimplanted eyes had improved visual acuity (P < .01). Implanted eyes had higher incidences of intraocular pressure elevation (> or = 10 mm Hg) than nonimplanted eyes (P < .01), and glaucoma surgery was required in 40% of implanted eyes vs 2% of nonimplanted eyes (P < .01). Cataracts were extracted in 93% of phakic implanted eyes vs 20% of phakic nonimplanted eyes (P < .01). CONCLUSIONS The FA implant significantly reduced uveitis recurrence and improved or stabilized visual acuity in subjects with noninfectious posterior uveitis. Most subjects required cataract extraction, and a significant proportion required intraocular pressure-lowering surgery. APPLICATION TO CLINICAL PRACTICE The FA implant provides an alternative therapy for prolonged control of inflammation in noninfectious posterior uveitis. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00407082.

CYTOKINES IN PROLIFERATIVE DIABETIC RETINOPATHY AND PROLIFERATIVE VITREORETINOPATHY

We determined whether interleukin-8, monocyte chemotactic protein-1, and macrophage-colony stimulating factor are present in the vitreous of patients with proliferative diabetic retinopathy (PDR) or proliferative vitreoretinopathy (PVR). The levels of these cytokines were measured by specific enzyme-linked immunoassays in vitreous from 30 patients with PDR, 13 patients with PVR, and 26 control individuals, including 10 cadaver eyes and 16 patients with idiopathic macular holes, idiopathic macular puckers, vitreous hemorrhages, or uncomplicated retinal detachments. Detectable levels of interleukin-8 were found in 90% of vitreous samples of patients with PDR, 85% with PVR, and 58% of control samples. IL-8 was significantly increased in PDR (mean +/- SEM; 25.0 +/- 5.3 ng/ml; p = 0.01), but not in PVR (11.9 +/- 3.9 ng/ml; p = 0.50) compared to control human vitreous (8.5 +/- 2.5 2.5 ng/ml). MCP-1 was detected in 90% of vitreous samples of patients with PDR, 92% with PVR, and 81% of control samples. MCP-1 was significantly increased in PDR (6.2 +/- 0.9 ng/ml, p = 0.001) and PVR (7.7 +/- 2.5 ng/ml, p = 0.001) over the levels in control vitreous (1.2 +/- 0.2 ng/ml). M-CSF was detected in 94% of vitreous samples of patients with PDR, 88% with PVR, and 92% from control vitreous. M-CSF was significantly elevated in PDR (32.3 +/- 8.3 ng/ml, p = 0.03), but not in PVR (23.6 +/- 12.8 ng/ml, p = 0.4) compared to control (10.7 +/- 3.5 ng/ml). Our results suggest that IL-8, MCP-1, and M-CSF participate in the pathogenesis of PDR and PVR.

Intravitreal triamcinolone acetonide in eyes with cystoid macular edema associated with central retinal vein occlusion.

PURPOSE To evaluate treatment of cystoid macular edema associated with central retinal vein occlusion with intravitreal triamcinolone acetonide. METHODS This study included 10 eyes of nine patients with perfused central retinal vein occlusion with visual acuity of 20/50 or worse. Following baseline evaluation, including best-corrected visual acuity, intraocular pressure (IOP), fluorescein angiography, and volumetric optical coherence tomography (VOCT), triamcinolone acetonide (4 mg in 0.1 ml) was injected into the vitreous cavity. RESULTS Mean duration from the time of diagnosis to the intravitreal injection was 15.4 months. All 10 eyes demonstrated biomicroscopic improvement in cystoid macular edema with corresponding improvement in VOCT measurements from a mean of 4.2 mm(3) preinjection to a mean of 2.6 mm(3) at last follow-up (P <.001). Mean best-corrected visual acuity improved from 58 letters (range, 37-72) at baseline to 78 letters (range, 50-100 letters) at last follow-up (average, 4.8 months). The visual acuity improvement was statistically significant (P =.01). Six eyes (60%) were > or =20/50. There were no significant complications. Three eyes (30%) without previous history of glaucoma required initiation of topical aqueous suppressant therapy for IOP elevation at last follow-up. One eye with a previous history of open-angle glaucoma required a trabeculectomy. CONCLUSIONS Intravitreal injection of triamcinolone acetonide appears to be effective in reducing cystoid macular edema associated with central retinal vein occlusion. This reduction often corresponded to an improvement in visual acuity. Further evaluation is warranted to assess its safety and efficacy in these eyes.

Ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for treatment of geographic atrophy in age-related macular degeneration

There is no treatment available for vision loss associated with advanced dry age-related macular degeneration (AMD) or geographic atrophy (GA). In a pilot, proof of concept phase 2 study, we evaluated ciliary neurotrophic factor (CNTF) delivered via an intraocular encapsulated cell technology implant for the treatment of GA. We designed a multicenter, 1-y, double-masked, sham-controlled dose-ranging study. Patients with GA were randomly assigned to receive a high-or low-dose implant or sham surgery. The primary endpoint was the change in best corrected visual acuity (BCVA) at 12 mo. CNTF treatment resulted in a dose-dependent increase in retinal thickness. This change was followed by visual acuity stabilization (loss of less than 15 letters) in the high-dose group (96.3%) compared with low-dose (83.3%) and sham (75%) group. A subgroup analysis of those with baseline BCVA at 20/63 or better revealed that 100% of patients in the high-dose group lost <15 letters compared with 55.6% in the combined low-dose/sham group (P = 0.033). There was a 0.8 mean letter gain in the high-dose group compared with a 9.7 mean letter loss in the combined low-dose/sham group (P = 0.0315). Both the implant and the implant procedure were well-tolerated. These findings suggest that CNTF delivered by the encapsulated cell technology implant appears to slow the progression of vision loss in GA, especially in eyes with 20/63 or better vision at baseline.

Diagnosis of vitreoretinal adhesions in macular disease with optical coherence tomography.

Purpose: To compare the relative incidence of vitreoretinal adhesions associated with partial vitreous separation within the macula diagnosed with optical coherence tomography (OCT) with that of those diagnosed with biomicroscopy. Methods: The authors obtained linear cross‐sectional retinal images using OCT in patients with selected macular diseases. Additional studies included biomicroscopy, fundus photography, fluorescein angiography, and B‐scan ultrasonography. Results: Optical coherence tomography was performed on 132 eyes of 119 patients. Vitreoretinal adhesions within the macula were identified using OCT in 39 eyes (30%) with the following diagnoses: idiopathic epiretinal membrane (n = 13), diabetic retinopathy (n = 7), idiopathic macular hole (n = 7), cystoid macular edema (n = 7), and vitreomacular traction syndrome (n = 5). Biomicroscopy identified vitreoretinal adhesions in only 11 eyes (8%). Two distinct vitreoretinal adhesion patterns were identified with OCT, each associated with partial separation of the posterior hyaloid face: focal (n = 25) and multifocal (n = 14). Conclusions: Optical coherence tomography is more sensitive than biomicroscopy in identifying vitreoretinal adhesions associated with macular disease.

Intravitreal aflibercept for diabetic macular edema: 100-week results from the VISTA and VIVID studies

PURPOSE To compare efficacy and safety of 2 dosing regimens of intravitreal aflibercept injection (IAI) with macular laser photocoagulation for diabetic macular edema (DME). DESIGN Two similarly designed, randomized, phase 3 trials, VISTA(DME) and VIVID(DME). PARTICIPANTS Patients (eyes; n=872) with type 1 or 2 diabetes mellitus who had DME with central involvement. METHODS Eyes received IAI 2 mg every 4 weeks (2q4), IAI 2 mg every 8 weeks after 5 monthly doses (2q8), or laser control. MAIN OUTCOME MEASURES The primary end point was mean change from baseline in best-corrected visual acuity (BCVA) at week 52. This report presents the 100-week results including mean change from baseline in BCVA, proportion of eyes that gained ≥15 letters, and proportion of eyes with a ≥2-step improvement in the Diabetic Retinopathy Severity Scale (DRSS) score. RESULTS Mean BCVA gain from baseline to week 100 with IAI 2q4, IAI 2q8, and laser control was 11.5, 11.1, and 0.9 letters (P < 0.0001) in VISTA and 11.4, 9.4, and 0.7 letters (P < 0.0001) in VIVID, respectively. The proportion of eyes that gained ≥15 letters from baseline at week 100 was 38.3%, 33.1%, and 13.0% (P < 0.0001) in VISTA and 38.2%, 31.1%, and 12.1% (P ≤ 0.0001) in VIVID. The proportion of eyes that lost ≥15 letters at week 100 was 3.2%, 0.7%, and 9.7% (P ≤ 0.0220) in VISTA and 2.2%, 1.5%, and 12.9% (P ≤ 0.0008) in VIVID. Significantly more eyes in the IAI 2q4 and 2q8 groups versus those in the laser control group had a ≥2 step improvement in the DRSS score in both VISTA (37.0% and 37.1% vs. 15.6%; P < 0.0001) and VIVID (29.3% and 32.6% vs. 8.2%; P ≤ 0.0004). In an integrated safety analysis, the most frequent serious ocular adverse event was cataract (2.4%, 1.0%, and 0.3% for 2q4, 2q8, and control). CONCLUSIONS In both VISTA and VIVID, the 52-week visual and anatomic superiority of IAI over laser control was sustained through week 100, with similar efficacy in the 2q4 and 2q8 groups. Safety in these studies was consistent with the known safety profile of IAI.