Michael S. Ip

A Randomized Trial Comparing the Efficacy and Safety of Intravitreal Triamcinolone With Observation to Treat Vision Loss Associated With Macular Edema Secondary to Central Retinal Vein Occlusion: The Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) Study Report 5

OBJECTIVE To compare the efficacy and safety of 1-mg and 4-mg doses of preservative-free intravitreal triamcinolone with observation for eyes with vision loss associated with macular edema secondary to perfused central retinal vein occlusion (CRVO). METHODS Multicenter, randomized, clinical trial of 271 participants. MAIN OUTCOME MEASURE Gain in visual acuity letter score of 15 or more from baseline to month 12. RESULTS Seven percent, 27%, and 26% of participants achieved the primary outcome in the observation, 1-mg, and 4-mg groups, respectively. The odds of achieving the primary outcome were 5.0 times greater in the 1-mg group than the observation group (odds ratio [OR], 5.0; 95% confidence interval [CI], 1.8-14.1; P = .001) and 5.0 times greater in 4-mg group than the observation group (OR, 5.0; 95% CI, 1.8-14.4; P = .001); there was no difference identified between the 1-mg and 4-mg groups (OR, 1.0; 95% CI, 0.5-2.1; P = .97). The rates of elevated intraocular pressure and cataract were similar for the observation and 1-mg groups, but higher in the 4-mg group. CONCLUSIONS Intravitreal triamcinolone is superior to observation for treating vision loss associated with macular edema secondary to CRVO in patients who have characteristics similar to those in the SCORE-CRVO trial. The 1-mg dose has a safety profile superior to that of the 4-mg dose. Application to Clinical Practice Intravitreal triamcinolone in a 1-mg dose, following the retreatment criteria applied in the SCORE Study, should be considered for up to 1 year, and possibly 2 years, for patients with characteristics similar to those in the SCORE-CRVO trial. Trial Registration clinicaltrials.gov Identifier: NCT00105027.

Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema

OBJECTIVE To report 3-year outcomes of patients who participated in a randomized trial evaluating 1-mg and 4-mg doses of preservative-free intravitreal triamcinolone compared with focal/grid photocoagulation for treatment of diabetic macular edema. METHODS Eyes with diabetic macular edema and visual acuities of 20/40 to 20/320 were randomly assigned to focal/grid photocoagulation or 1 mg or 4 mg of triamcinolone. At the conclusion of the trial, 3-year follow-up data were available in 306 eyes. RESULTS Between 2 years (time of the primary outcome) and 3 years, more eyes improved than worsened in all 3 treatment groups. Change in visual acuity letter score from baseline to 3 years was +5 in the laser group and 0 in each triamcinolone group. The cumulative probability of cataract surgery by 3 years was 31%, 46%, and 83% in the laser and 1-mg and 4-mg triamcinolone groups, respectively. Intraocular pressure increased by more than 10 mm Hg at any visit in 4%, 18%, and 33% of eyes, respectively. CONCLUSIONS Results in a subset of randomized subjects who completed the 3-year follow-up are consistent with previously published 2-year results and do not indicate a long-term benefit of intravitreal triamcinolone relative to focal/grid photocoagulation in patients with diabetic macular edema similar to those studied in this clinical trial. Most eyes receiving 4 mg of triamcinolone as given in this study are likely to require cataract surgery. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00367133.

Anti–Vascular Endothelial Growth Factor Pharmacotherapy for Age-Related Macular Degeneration: A Report by the American Academy of Ophthalmology

OBJECTIVE To examine the evidence about the safety and efficacy of anti-vascular endothelial growth factor (VEGF) pharmacotherapies for the treatment of neovascular age-related macular degeneration (AMD). DESIGN Literature searches were conducted in May and October 2007 in PubMed with no date restrictions, limited to articles published in English, and in the Cochrane Central Register of Controlled Trials without a language limitation and yielded 310 citations. The first author reviewed the abstracts of these articles and selected 73 articles of possible clinical relevance for review by the panel. The panel deemed 64 of these articles sufficiently clinically relevant to review in full text and assigned ratings of level of evidence to each of the selected articles with the guidance of the panel methodologists. RESULTS Eleven studies provided level I evidence for intravitreal pegaptanib and ranibizumab for neovascular AMD; there were no studies rated level I for bevacizumab for neovascular AMD. Five studies were rated as level II, which included studies of ranibizumab and bevacizumab, and the remaining 38 articles retrieved were rated as level III. The studies do not provide information about long-term results or the value (comparative effectiveness) and cost-effectiveness of combined therapies. CONCLUSIONS Review of the available literature to date suggests that anti-VEGF pharmacotherapy, delivered by intravitreal injection, is a safe and effective treatment for neovascular AMD for up to 2 years. There is level I evidence to support this conclusion for pegaptanib and ranibizumab, but none for bevacizumab at this time.

Long-term Effects of Ranibizumab on Diabetic Retinopathy Severity and Progression

OBJECTIVE To evaluate effects of intravitreal ranibizumab on diabetic retinopathy (DR) severity over time in 2 phase 3 clinical trials (RIDE, NCT00473382; RISE, NCT00473330) of ranibizumab for diabetic macular edema. METHODS Participants with diabetic macular edema (n=759) were randomized to monthly sham, 0.3-mg ranibizumab, or 0.5-mg ranibizumab intravitreal injections. Macular laser was available per protocol-specified criteria. Fundus photographs, taken at baseline and periodically, were graded by a central reading center; clinical examinations were performed monthly. The main outcome measures of this report are secondary/exploratory analyses including a 2-step or more and 3-step or more change on the Early Treatment Diabetic Retinopathy Study severity scale in the study eye and a composite DR progression outcome including photographic changes plus clinically important events such as occurrence of vitreous hemorrhage or need for panretinal laser. RESULTS At 2 years, the percentage of participants with DR progression (worsening by ≥ 2 or ≥ 3 steps) was significantly reduced in ranibizumab-treated eyes compared with sham-treated eyes, and DR regression (improving by ≥ 2 or ≥ 3 steps) was significantly more likely. The cumulative probability of clinical progression of DR as measured by the composite outcome at 2 years was 33.8% of sham-treated eyes compared with 11.2% to 11.5% of ranibizumab-treated eyes. CONCLUSIONS Intravitreal ranibizumab reduced the risk of DR progression in eyes with diabetic macular edema, and many ranibizumab-treated eyes experienced improvement in DR severity. Because these results are exploratory, the use of intravitreal ranibizumab specifically to reduce DR progression or cause DR regression requires further study.

Small-gauge pars plana vitrectomy: a report by the American Academy of Ophthalmology.

OBJECTIVE To review available peer-reviewed publications to evaluate the safety profile and visual outcomes associated with small-gauge pars plana vitrectomy. METHODS Literature searches of the PubMed and the Cochrane Library databases were last conducted on August 5, 2009, with no date restrictions. The searches were limited to articles published in English. These searches retrieved 328 articles, of which 76 were deemed topically relevant and rated according to strength of evidence. RESULTS On the basis of level II and level III evidence, the overall safety profile of small-gauge pars plana vitrectomy is similar to that established for conventional 20-gauge pars plana vitrectomy and provides comparable visual acuity results. An increased incidence of infectious endophthalmitis after 25-gauge vitrectomy was reported in 2 comparative studies, but this was not found in multiple, larger, more recent studies, perhaps due to modifications in case selection and surgical technique over time. Compared with 20-gauge vitrectomy, small-gauge vitrectomy is associated with significantly lower levels of patient discomfort and ocular inflammation, and the time required for improvement in visual acuity is shorter. CONCLUSIONS The technological advances of small-gauge vitrectomy seem to afford visual benefit comparable with that seen with traditional 20-gauge surgery, with more rapid healing, less discomfort, and an acceptably low incidence of adverse events comparable with those observed with conventional 20-gauge vitrectomy. As surgical techniques evolve and clinical experience grows, continued close surveillance is necessary for an accurate assessment of complications.

SCORE Study Report 1: Baseline Associations between Central Retinal Thickness and Visual Acuity in Patients with Retinal Vein Occlusion

OBJECTIVE To investigate the relationship between baseline center point retinal thickness measured by optical coherence tomography (OCT) and best-corrected visual acuity in eyes with macular edema associated with retinal vein occlusion and to investigate other factors associated with baseline visual acuity letter score. DESIGN The Standard Care versus COrticosteroid for REtinal Vein Occlusion (SCORE) Study includes 2 multicenter, randomized clinical trials: one evaluating participants with central retinal vein occlusion (CRVO) and the other evaluating participants with branch retinal vein occlusion (BRVO). PARTICIPANTS After omitting 17 participants with missing or unreliable OCT measurements, analyses proceeded with 665 enrolled SCORE Study participants (665 eyes), including 262 with CRVO and 403 with BRVO. METHODS At baseline, center point thickness was measured by OCT (Stratus OCT 3 [n=663] and OCT2 [n=2]; Carl Zeiss Meditech, Dublin, CA), and visual acuity was measured by the electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) methodology. MAIN OUTCOME MEASURES Center point thickness and best-corrected E-ETDRS visual acuity letter score. RESULTS The correlation coefficient for the association between baseline OCT-measured center point thickness and best-corrected E-ETDRS visual acuity letter score is -0.27 (95% confidence limit: -0.38 to -0.16) for participants in the CRVO trial and -0.28 (95% confidence limit: -0.37 to -0.19) in the BRVO trial. Regression modeling estimated the following decrease in baseline visual acuity letter score for every 100-microm increase in OCT-measured center point thickness: 1.7 letters (P=0.0007) for CRVO and 1.9 letters (P<0.0001) for BRVO. On the basis of multivariate regression models, baseline factors significantly associated (P<0.05, after adjusting for multiple testing) with baseline visual acuity letter score include age and duration of macular edema for CRVO participants and center point thickness and presence of cystoid spaces for BRVO participants. CONCLUSIONS The correlation between OCT-measured center point thickness and visual acuity letter score is modest. OCT-measured center point thickness represents a useful tool for the detection and monitoring of macular edema in retinal vein occlusion, but it cannot reliably substitute for visual acuity measurements.

Anti–Vascular Endothelial Growth Factor Pharmacotherapy for Diabetic Macular Edema: A Report by the American Academy of Ophthalmology

OBJECTIVE To review the evidence regarding the safety and efficacy of current anti-vascular endothelial growth factor (VEGF) pharmacotherapies for the treatment of diabetic macular edema (DME). METHODS Literature searches last were conducted in September 2011, in PubMed with no date restrictions, limited to articles published in English, and in the Cochrane Library without a language limitation. The combined searches yielded 532 citations, of which 45 were deemed clinically relevant for the authors to review in full text and to assign ratings of level of evidence to each of the selected studies with the guidance of the panel methodologists. RESULTS At this time, there are 5 studies that provide level I evidence for intravitreal ranibizumab, alone or in combination with other treatments for DME. There is also 1 study that provides level I evidence for intravitreal pegaptanib sodium for DME. Nine studies reviewed were rated as level II, and 2 additional studies reviewed were graded as level III. Most studies do not provide information about long-term results (i.e., more than 2 years of follow-up) or the comparative efficacy of anti-VEGF pharmacotherapies. CONCLUSIONS Review of the available literature indicates that anti-VEGF pharmacotherapy, delivered by intravitreal injection, is a safe and effective treatment over 2 years for DME. Further evidence is required to support the long-term safety of these pharmacotherapies and their comparative efficacy.

Factors Associated with Improvement and Worsening of Visual Acuity 2 Years after Focal/Grid Photocoagulation for Diabetic Macular Edema

PURPOSE To identify factors associated with the visual acuity outcome after focal/grid photocoagulation for diabetic macular edema (DME) among eyes randomized to the focal/grid photocoagulation treatment group within the Diabetic Retinopathy Clinical Research Network (DRCR.net) trial comparing triamcinolone with focal/grid laser. DESIGN Multicenter, randomized, clinical trial. PARTICIPANTS Three hundred thirty eyes with DME assigned to the focal/grid photocoagulation group, visual acuity 20/40 to 20/320, and optical coherence tomography (OCT) central subfield thickness > or =250 microns. METHODS Eyes were treated with a protocol-defined photocoagulation technique, which was repeated at 4-month intervals for persistent or recurrent edema. Separate logistic regression models were used to evaluate the associations of demographic, clinical, OCT, and fundus photographic variables with visual acuity improvement or worsening of > or =10 letters from baseline to 2 years. The association of the initial visual acuity outcome after treatment with the subsequent visual acuity course also was evaluated. MAIN OUTCOME MEASURES Visual acuity measured with the electronic Early Treatment Diabetic Retinopathy Study method. RESULTS Worse baseline visual acuity was the only factor found to be associated with more frequent visual acuity improvement (P<0.001), and both greater baseline OCT-measured retinal volume (P = 0.001) and better baseline visual acuity (P = 0.009) were found to be associated with more frequent visual acuity worsening. Visual acuity outcomes were similar in eyes with and without prior macular or panretinal photocoagulation. The initial visual acuity outcome at 4 months was not generally predictive of the subsequent course. Many eyes that worsened > or =10 letters from baseline to 4 months subsequently improved, and many eyes that initially improved, subsequently worsened. CONCLUSIONS At this time, focal/grid photocoagulation remains the standard management for DME and these results do not alter this paradigm.

Exploratory Analysis of Diabetic Retinopathy Progression Through 3 Years in a Randomized Clinical Trial That Compares Intravitreal Triamcinolone Acetonide With Focal/Grid Photocoagulation

OBJECTIVE To compare the effect of intravitreal triamcinolone acetonide with focal/grid photocoagulation on the progression of diabetic retinopathy. METHODS We performed an exploratory analysis of participants with diabetic macular edema randomly assigned to receive laser therapy or intravitreal triamcinolone acetonide (1 or 4 mg). Fundus photographs were obtained at baseline and 1, 2, and 3 years. The main outcome measure was progression to proliferative diabetic retinopathy or worsening of 2 or more severity levels on reading-center masked assessment of 7-field fundus photographs, plus additional eyes that received panretinal photocoagulation or had a vitreous hemorrhage. RESULTS From July 15, 2004, through May 5, 2006, 840 eyes from 693 participants were enrolled in the study and randomly assigned to receive laser therapy (n = 330), 1 mg of triamcinolone acetonide (n = 256), or 4 mg of triamcinolone acetonide (n = 254). The cumulative probability of progression of retinopathy at 2 years was 31% (laser group), 29% (1-mg group), and 21% (4-mg group) (P = .64 in the 1-mg group and .005 in the 4-mg group compared with the laser group). These differences appeared to be sustained at 3 years. CONCLUSIONS Intravitreal triamcinolone acetonide (4 mg) appeared to reduce the risk of progression of diabetic retinopathy. Given the exploratory nature of this analysis and because intravitreal triamcinolone adverse effects include cataract formation and glaucoma, use of this treatment merely to reduce the rates of progression of proliferative diabetic retinopathy or worsening of the level of diabetic retinopathy does not seem warranted at this time.

Baseline predictors of visual acuity and retinal thickness outcomes in patients with retinal vein occlusion: Standard Care Versus COrticosteroid for REtinal Vein Occlusion Study report 10.

OBJECTIVE To investigate baseline factors associated with visual acuity and central retinal thickness outcomes in patients with macular edema secondary to retinal vein occlusion in the Standard Care versus COrticosteroid for REtinal Vein Occlusion (SCORE) Study. DESIGN Two multicenter, randomized clinical trials: one evaluating participants with central retinal vein occlusion (CRVO) and one evaluating participants with branch retinal vein occlusion (BRVO). PARTICIPANTS Participants with follow-up data of 1 year or more, including 238 with CRVO and 367 with BRVO. METHODS Visual acuity was measured by the electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) method, and central retinal thickness was measured by optical coherence tomography (OCT). Regression analysis related these outcomes to 20 baseline measures. Multiple P values were adjusted to control the false discovery rate. MAIN OUTCOME MEASURES Outcome measures of visual acuity letter score included absolute change from baseline, a gain of ≥ 15 from baseline, and a loss of ≥ 15 from baseline. Outcome measures of center point thickness included absolute change from baseline, a measurement of ≤ 250 μm, and a measurement of ≥ 500 μm. Outcomes were assessed at 1 and 2 years. RESULTS For CRVO and BRVO, younger age was associated with improved visual acuity and central retinal thickness outcomes. For CRVO, triamcinolone treatment and less severe anatomic abnormalities of the retina (center point thickness and areas of retinal hemorrhage, thickening, and fluorescein leakage) were predictive of better visual acuity outcomes. For BRVO, no history of coronary artery disease was predictive of improved visual acuity outcomes. For center point thickness outcomes, shorter duration of macular edema was associated with improvement in both disease entities. For CRVO, higher baseline visual acuity letter score was predictive of favorable OCT outcomes. For BRVO, lower baseline visual acuity letter score, presence of dense macular hemorrhage, and no prior grid photocoagulation were predictive of favorable OCT outcomes. CONCLUSIONS Several factors were predictive of better visual acuity outcomes and more favorable OCT outcomes, including younger age and shorter duration of macular edema, respectively. These factors may assist clinicians in predicting disease course for patients with CRVO and BRVO.