Vascular Safety of Ranibizumab in Patients With Diabetic Macular Edema: A Pooled Analysis of Patient-Level Data From Randomized Clinical Trials.

Importance: Patients with diabetic macular edema (DME) are at high risk of vascular complications, including stroke and myocardial infarction (MI). Concerns have been raised that intravitreal dosing of vascular endothelial growth factor inhibitors in DME could be associated with an increase in cardiovascular and cerebrovascular adverse events. Objective: To evaluate the cardiovascular and cerebrovascular safety of ranibizumab, 0.5 mg and 0.3 mg, compared with sham with and without laser in DME. Data Sources: Patient-level data from 6 randomized, double-masked, sham- and laser-controlled clinical trials. Study Selection: Company-sponsored (Genentech or Novartis) studies in DME completed as of December 31, 2013. Data Extraction and Synthesis: Pairwise comparisons (ranibizumab, 0.5 mg, vs sham and laser; ranibizumab, 0.3 mg, vs sham) were performed using Cox proportional hazard regression (hazard ratios, 95% CIs) and rates per 100 person-years. Data analysis was conducted from June 1 to July 15, 2015. Main Outcomes and Measures: Standardized Medical Dictionary for Regulatory Activities queries and extended searches were prospectively defined to identify relevant safety end points, including arterial thromboembolic events, MI, stroke or transient ischemic attack, vascular deaths, and major vascular events as defined by the Antiplatelet Trialists' Collaboration (APTC). Results: Overall, 936 patients were treated with ranibizumab, 0.5 mg; 250 patients with ranibizumab, 0.3 mg; and 581 patients with sham/laser. The hazard ratios associated with all pairwise comparisons included 1 for all key cardiovascular and cerebrovascular safety end points. For ranibizumab, 0.5 mg, vs sham/laser and ranibizumab, 0.3 mg, vs sham, the hazard ratios were, respectively, arterial thromboembolic events, 1.05 (95% CI, 0.66-1.68) and 0.78 (95% CI, 0.43-1.40); MI, 0.84 (95% CI, 0.41-1.72) and 0.94 (95% CI, 0.43-2.06); stroke or transient ischemic attack, 0.94 (95% CI, 0.44-1.99) and 0.53 (95% CI, 0.19-1.42); stroke (excluding transient ischemic attack), 1.63 (95% CI, 0.65-4.07) and 0.59 (95% CI, 0.14-2.46); vascular death, 2.17 (95% CI, 0.57-8.29) and 2.51 (95% CI, 0.49-12.94); and APTC-defined events, 1.09 (95% CI, 0.63-1.88) and 1.00 (95% CI, 0.51-1.96). Conclusions and Relevance: This pooled analysis includes 1 of the largest patient-level data sets on treatment of DME with ranibizumab. Although still underpowered to detect small differences for infrequent events, such as stroke, the findings suggest that intravitreous ranibizumab does not increase the risk of systemic vascular events. However, uncertainty remains for patients with DME who are at high risk for vascular disease and were not included in these trials.

The effect of intensive education on concordance with the Age-Related Eye Disease Study (AREDS) recommendations in a tertiary referral practice.

BACKGROUND/AIMS: The Age-Related Eye Disease Study (AREDS) showed that supplementation with their formula led to a significant decrease in progression of age-related macular degeneration (AMD). This study aims to assess the effect of different education protocols on concordance with the trial recommendations in two retinal clinics. METHODS: A prospective controlled survey of concordance with the AREDS recommendations in two retinal clinics was administered to 330 patients with AREDS category 3 or 4 AMD. The results were evaluated to assess the effect of differing levels of patient education. In clinic 1, there was a formal policy of giving the patient both verbal and written instructions and verbal repetition of these instructions from each staff member on each patient visit; in clinic 2, there was no specific education policy. RESULTS: Clinic 1 had a concordance rate of 81.6% and clinic 2 of 44.1%. There were no significant differences in the patient demographics between the two clinics. CONCLUSION: A high concordance rate can be achieved in clinical practice with rigorous patient education that includes a policy of having continual repetition of instructions.

Lesion morphology in age-related macular degeneration and its therapeutic significance.

OBJECTIVES: To quantify and categorize the lesions of neovascular age-related macular degeneration on the basis of fluorescein angiographic morphology. METHODS: We retrospectively reviewed 3580 consecutive cases of neovascular age-related macular degeneration. The lesions were graded in terms of the location, size, and composition and categorized according to the lesion components. RESULTS: A comprehensive schema for lesion description and categorization is presented. There were 2642 subfoveal (73.8%), 658 juxtafoveal (18.4%), and 276 extrafoveal (7.7%) lesions. After disciform lesions were excluded, 1337 subfoveal (72.3%), 580 juxtafoveal (88.1%), and 242 extrafoveal lesions (87.7%) consisted of at least 50% choroidal neovascularization, most of which included a classic or an occult component but not both. Subfoveal lesions (mean size, 2.82 Macular Photocoagulation Study disc areas) were significantly larger than juxtafoveal (mean size, 0.89 Macular Photocoagulation Study disc areas) or extrafoveal lesions (mean size, 1.04 Macular Photocoagulation Study disc areas) (Kruskal-Wallis, P<.001), but overall the lesions were substantially smaller than those found in the major trials. It is estimated that photodynamic therapy or photocoagulation may be offered to one half to two thirds of all patients with nondisciform neovascular age-related macular degeneration. CONCLUSION: The smaller lesion size and low proportion of mixed choroidal neovascularization lesions suggest that treatment benefit and eligibility may be greater in the clinical setting than previously thought.

Visual outcomes following vitrectomy and peeling of epiretinal membrane.

BACKGROUND: Visual outcomes of patients following vitrectomy and peeling of visually significant epiretinal membranes were assessed to determine the influence of specific perioperative factors and surgical complications on final visual acuity and functional vision. METHODS: In an unmatched, consecutive surgical series, vitrectomy and membrane peeling were performed on 125 eyes of 123 patients with visually significant macular epiretinal membranes. Patients were followed for 6-36 months. Visual outcome measures included postoperative logMAR visual acuity, change in visual acuity and functional vision tasks evaluated by questionnaire. Perioperative factors including duration of symptoms, preoperative visual acuity, aetiology, membrane type and leakage on fundal fluorescein angiogram were correlated with final visual outcomes. RESULTS: Visual acuity improved by a mean of 0.31 A+/- 0.21 units (three lines of vision). In 104 cases (83%), visual acuity improved in patients by two lines or more, with 20 cases (16%) having unchanged acuity and one case (1%) having worse acuity. Ninety-three per cent of interviewed cases reported improvement in functional vision, especially reduction of distortion. Cataract was observed in 52 cases (52% of phakic eyes) postoperatively compared with 19 cases (19%) preoperatively. Postoperative visual acuity correlated with preoperative visual acuity. Patients with worse preoperative vision recorded greater visual improvement following surgery. No other perioperative factors were found to have a prognostic value in this study. CONCLUSION: Epiretinal membrane peeling improves vision in the majority of patients with significant symptoms, even if preoperative visual acuity is not substantially reduced. Surgery improves functional vision including metamorphopsia not measurable by visual acuity, and thus assessment of functional vision should be included in surgical case planning.

Dynamic atypical optic nerve coloboma associated with transient macular detachment.

PURPOSE: Macular schisis or detachment is frequently observed in eyes with optic pits or colobomas. Although spontaneous resolution of the maculopathy has been reported, concurrent changes in the optic nerve coloboma have not. We report three cases of atypical optic nerve colobomas in which dynamic optic nerve changes coincide with the development and subsequent resolution of the associated maculopathy. METHODS: We reviewed the records of three patients with dynamic optic nerve changes associated with maculopathy. All patients were observed for at least 6 months. Fundus photography and fluorescein angiography were used to document the optic nerve and macular changes. RESULTS: Three patients were noted to have macular detachments without apparent optic nerve excavation. With observation, the maculopathy spontaneously resolved in each case. We documented concurrent optic nerve changes whereby atypical optic nerve colobomas became apparent over several months in all cases. In one case, we noted the simultaneous development of maculopathy in association with obscuration of a prior disc anomaly. None of the eyes had a posterior vitreous detachment. We could not identify any associated systemic conditions or reproduce the findings with external stimulation. Initial Snellen acuity ranged from 20/60 to 20/200. Final Snellen acuity ranged from 20/20 to 20/40. CONCLUSIONS: Fluctuating optic nerve changes may occur in the setting of atypical optic nerve coloboma and associated maculopathy. In cases of macular schisis or detachment where an optic nerve coloboma is not readily apparent, and no other causes are identified, consideration of a period of observation prior to therapeutic intervention seems appropriate.

Case series outcomes at 1 week following verteporfin photodynamic therapy.

PURPOSE: To examine the choroidal neovascularization (CNV) fluorescein angiographic perfusion and visual acuity 1 week after photodynamic therapy (PDT) with verteporfin (Visudyne, Novartis AG, Switzerland) on predominantly classic, subfoveal lesions in age-related macular degeneration (AMD). METHOD: A retrospective case series study was conducted on the 1-week outcome of PDT treatment of 76 of 79 consecutive patients with the subfoveal, predominantly classic CNV form of AMD. Leakage from CNV was assessed by fluorescein angiography and best-corrected visual acuity determined on projected Snellen charts using a standardized protocol. RESULTS: One week after PDT treatment, absence of fluorescein leakage from CNV was observed in 100% of the 76 patients. Visual acuity improved (at least a three-line gain) in 11 patients (15%), remained unchanged (less than a three-line gain or loss) in 64 patients (84%), and deteriorated (at least a three-line loss) in only one patient (1%). CONCLUSION: The absence of fluorescein leakage from classic CNV at 1 week in all cases was consistent with the published outcome of the clinical Phase I and II PDT trials. Further, vision loss 1 week after PDT for predominantly classic CNV was very uncommon. Therefore 1-week post-PDT angiography is unnecessary for predominantly classic CNV in patients with AMD.

Limited macular translocation for subfoveal choroidal neovascularization in age-related macular degeneration.

PURPOSE: To examine the safety and efficacy of limited macular translocation followed by laser photocoagulation in the management of subfoveal choroidal neovascularization (CNV) in age-related macular degeneration (AMD). METHODS: A prospective study was conducted on eight consecutive patients undergoing limited macular translocation followed by laser photocoagulation for the treatment of subfoveal classic CNV form of AMD. Patients were followed up for a minimum of 12 months. The magnitude of foveal translocation, visual outcomes and complications were assessed. RESULTS: In all cases the fovea was successfully translocated inferiorly, with a median displacement of 1.1 mm. Thermal laser photocoagulation was subsequently performed in all cases. Visual acuity improved in five eyes, remained unchanged in two eyes and worsened in one eye. The mean improvement in visual acuity was by 0.19 logMAR. At 12 months, six of the eight patients (75%) achieved Snellen visual acuity of at least 6/15, with four patients (50%) achieving Snellen visual acuity of 6/9. CONCLUSION: In this small case series, limited macular translocation was found to be an effective and reproducible means of treating small well-defined subfoveal CNV.

Cup-to-disc ratio, intraocular pressure, and primary open-angle glaucoma in retinal venous occlusion.

PURPOSE: To investigate the association of cup-to-disc ratio (CDR), intraocular pressure (IOP), and primary open-angle glaucoma (POAG) with the site of retinal venous occlusion (RVO) and optic nerve head swelling (ONHS). DESIGN: Prospective observational case series. PARTICIPANTS: Four hundred fifty consecutive cases from a single tertiary referral center. METHODS: Fundus photography of the retinopathy, 30 degrees stereo photography of the optic disc, and Goldmann applanation tonometry were the main parameters studied. The diagnosis of POAG was obtained from the referring ophthalmologist. MAIN OUTCOME MEASURES: The main outcome measures were the CDR, measured vertically through the center of the optic disc, and the site of RVO, identified as an arteriovenous (AV) crossing, optic cup, or optic nerve. Retinal venous occlusions occurring within the optic nerve were subdivided on the basis of the presence or absence of ONHS. RESULTS: There were poor correlations between CDR and IOP (r = 0.18; P = 0.000209) and CDR and age (r = 0.21; P = 0.000012). There were 197 AV crossing-sited RVOs (AV-RVOs) (43.8%) and 46 optic cup (OC)-sited RVOs (10.2%). The remainder occurred within the optic nerve; the ONHS group had 80 cases (17.8%) and the nonoptic nerve head swelling group (NONHS) had 127 cases (28.2%). The OC-RVO group tended to be the oldest of the four groups, whereas the ONHS group was the youngest (P < 0.000001). The mean CDR was significantly higher in the OC-RVO (0.65) compared with the rest of the groups (0.45-0.48). The proportion of cases with CDR > or = 0.7 was significantly higher in the OC-RVO group (39.1%) compared with the rest of the groups (0-6.3%). There was a trend (P = 0.000012) for IOP in the OC-RVO group (19.0 mmHg) and NONHS group (17.6 mmHg); the proportion of cases with IOP more than 21 mmHg was also higher in these cases (P = 0.00033). The prevalence of POAG was highest (P < 0.000001) in the OC-RVO group (39.1%) followed by the NONHS group (18.1%), ONHS group (8.8%), and AV-RVO (4.1%) group, respectively. CONCLUSIONS: Optic cup and optic nerve-sited RVO without ONHS are associated with raised IOP and may share a common management strategy aimed at controlling ocular pressure. Glaucomatous optic disc cupping, in contrast, seems to be important in the OC-sited RVO group only. Intraocular pressure, POAG, and glaucomatous optic disc cupping do not significantly seem to contribute to the development of RVO at an AV crossing or when the occlusion occurs within the optic nerve in association with ONHS.