Systemic Safety in Ranibizumab-Treated Patients with Neovascular Age-Related Macular Degeneration: A Patient-Level Pooled Analysis

Topic This study evaluated the cardiovascular/cerebrovascular safety profile of ranibizumab 0.5 mg versus sham ± verteporfin in patients with neovascular age-related macular degeneration (nAMD). In addition, comparisons of ranibizumab 0.3 mg with sham and ranibizumab 0.5 mg to 0.3 mg were performed. Clinical Relevance Intravitreal anti–vascular endothelial growth factor (VEGF) agents carry potential increased systemic risks, including cardiovascular or cerebrovascular events. Pooled safety analyses allow better interpretation of safety outcomes seen in individual clinical trials, especially for less common events. To our knowledge, this is the largest patient-level pooled analysis of patients with nAMD treated with ranibizumab. Methods Patient-level pooled analysis of data from 7 Genentech- and Novartis-sponsored phase II, III, and IV studies in nAMD that were completed by December 31, 2013. Pairwise comparisons (primary comparison: ranibizumab 0.5 mg [globally approved dose for nAMD] vs. sham or verteporfin) were performed using Cox proportional hazard regression (hazard ratios [HRs], 95% confidence intervals [CIs]) and rates per 100 patient-years. Standardized Medical Dictionary for Regulatory Activities queries (SMQs) and extended searches were used to identify relevant safety endpoints, including arterial thromboembolic events (ATEs), myocardial infarction (MI), stroke or transient ischemic attack (TIA), stroke (excluding TIA), vascular deaths, and major vascular events as defined by the Antiplatelet Trialists' Collaboration (APTC). Results The HRs (95% CIs) for the primary comparison of ranibizumab 0.5 mg (n=480) versus sham or verteporfin (n=462) were 1.16 (0.72–1.88) for ATE, 1.33 (0.59–2.97) for MI, 1.43 (0.54–3.77) for stroke excluding TIA, 1.25 (0.61–2.55) for stroke or TIA, 0.57 (0.18–1.78) for vascular death, and 1.12 (0.64–1.98) for APTC events. Hazard ratio 95% CIs included 1, indicating no significant treatment differences, for all endpoints for comparison of ranibizumab 0.5 mg versus sham or verteporfin. Conclusions The rates of cardiovascular and cerebrovascular events were low in these patients with nAMD and not clinically meaningfully different for patients treated with ranibizumab 0.5 mg versus sham or verteporfin, which supports the favorable benefit–risk profile of ranibizumab in the patient population with nAMD. Pooling these studies allows an analysis with higher power and precision compared with individual study analyses

Diabetic Retinopathy Management

Strict control of blood glucose and blood pressure is critical for reduction of the incidence and progression of diabetic retinopathy (DR). Follow-up of patients with diabetes mellitus is protocol based and not based solely on the presence of symptoms. Staging of the level of DR (mild, moderate, or severe nonproliferative DR vs. proliferative DR, PDR) drives the follow-up interval. The most common cause of visual loss in diabetic patients is diabetic macular edema (DME). The results of multicenter, randomized studies suggest that the best visual results for DME currently are achieved with intravitreal ranibizumab injections ± focal laser photocoagulation. Results using bevacizumab seem quite comparable to those with ranibizumab. In addition to treating DME, this approach also seems to reduce the likelihood of progression of DR. Selected patients also may benefit from intravitreal steroid treatment + focal laser therapy, but there is a relatively higher rate of glaucoma and cataract formation. Panretinal photocoagulation is currently the most effective treatment for high-risk PDR. Panretinal photocoagulation also should be considered for patients with severe nonproliferative DR and early PDR, particularly if follow-up cannot be assured and/or if the patient has type 2 diabetes mellitus. Pars plana vitrectomy is used to manage severe complications of DR such as nonclearing vitreous hemorrhage, severe fibrovascular proliferation, and retinal detachment. Adjunctive anti-vascular endothelial growth factor agents might enhance those results in selected subsets of patients

Review of Emerging Treatments for Age-Related Macular Degeneration

In the era of pathway-based therapy, all treatments for AMD will address some step in the pathway that leads from early to late AMD. Steps in AMD pathogenesis that appear to be good targets for drug development include the following: (1) oxidative damage, (2) lipofuscin accumulation, (3) chronic inflammation, (4) mutations in the complement pathway, (5) mitochondrial damage, (6) Alu RNA accumulation in RPE, and (7) BMP-4 accumulation in RPE. Steps in neovascularization that can be targeted for drug development and combination therapy include the following: (1) angiogenic factor production, (2) extracellular factor release, (3) binding of factors to extracellular receptors (and activation of intracellular signaling after receptor binding), (4) endothelial cell activation (and basement membrane degradation), (5) endothelial cell proliferation, (6) directed endothelial cell migration, (7) extracellular matrix remodeling, (8) tube formation, and (9) vascular stabilization. Combination therapy will likely supplant monotherapy as the treatment of choice because the clinical benefits will likely be superior in preventing the complications of AMD

Treatment of Dry Age-Related Macular Degeneration

We have entered the era of pathway-based therapy for the early and late manifestations of AMD. Each of the treatments mentioned in this chapter acts at a putative step in the pathogenesis of AMD. Steps that have been targeted thus far include oxidative damage, lipofuscin accumulation, chronic inflammation (including complement activation), extracellular matrix changes (e.g. beta-amyloid accumulation), and apoptosis. In principle, these therapies can be combined ('combination therapy'), which may lead to synergistic effects that include better visual outcome, less likelihood for 'escape' (i.e. drug resistance), and less frequent treatment. Copyright (C) 2012 S. Karger AG, Base

Pathway-based therapies for age-related macular degeneration: an integrated survey of emerging treatment alternatives

To review treatments under development for age-related macular degeneration (AMD) in the context of current knowledge of AMD pathogenesis. Review of the scientific literature published in English. Steps in AMD pathogenesis that appear to be good targets for drug development include 1) oxidative damage; 2) lipofuscin accumulation; 3) chronic inflammation; 4) mutations in the complement pathway; and 5) noncomplement mutations that influence chronic inflammation and/or oxidative damage (e.g., mitochondria and extracellular matrix structure). Steps in neovascularization that can be targeted for drug development and combination therapy include 1) angiogenic factor production; 2) factor release; 3) binding of factors to extracellular receptors (and activation of intracellular signaling after receptor binding); 4) endothelial cell activation (and basement membrane degradation); 5) endothelial cell proliferation; 6) directed endothelial cell migration; 7) extracellular matrix remodeling; 8) tube formation; and 9) vascular stabilization. The era of pathway-based therapy for the early and late stages of AMD has begun. At each step in the pathway, a new treatment could be developed, but complete inhibition of disease progression will likely require a combination of the various treatments. Combination therapy will likely supplant monotherapy as the treatment of choice because the clinical benefits (visual acuity and frequency of treatment) will likely be superior to monotherapy in preventing the late-stage complications of AMD

Pediatric open globe injury: A review of the literature

Open globe injury (OGI) is a severe form of eye trauma estimated at 2-3.8/100,000 in the United States. Most pediatric cases occur at home and are the result of sharp object penetration. The aim of this article is to review the epidemiology, diagnosis, management, and prognosis of this condition by conducting a systematic literature search with inclusion of all case series on pediatric OGI published between 1996 and 2015. Diagnosis of OGI is based on patient history and clinical examination supplemented with imaging, especially computed tomography when indicated. Few prospective studies exist for the management of OGI in pediatric patients, but adult recommendations are often followed with success. The main goals of surgical management are to repair the open globe and remove intraocular foreign bodies. Systemic antibiotics are recommended as medical prophylaxis against globe infection, or endophthalmitis. Other complications are similar to those seen in adults, with the added focus of amblyopia therapy in children. Severe vision decline is most likely due to traumatic cataracts. The ocular trauma score, a system devised to predict final visual acuity (VA) in adults, has proven to be of prognostic value in pediatric OGI as well. Factors indicating poor visual prognosis are young age, poor initial VA, posterior eye involvement, long wound length, globe rupture, lens involvement, vitreous hemorrhage, retinal detachment, and endophthalmitis. A thorough understanding of OGI and the key differences in epidemiology, diagnosis, management, and prognosis between adults and children is critical to timely prevention of posttraumatic vision loss early in life