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Abstract
Age-related macular degeneration (AMD) is a multifactorial disorder with heterogeneous clinical features. Based on clinical and multimodal imaging studies, AMD has been classified with a great extent of consensus into early-stage, that is, from medium- to large-sized drusen and retinal pigmentary abnormalities and late-stage, that is, atrophic and neovascular. At different stages, multiple cell types of retina and choroid, as well as immune cells, interact and participate in pathophysiological events at the macular region. In the macular milieu, dysregulated events in the oxidative stress/ROS generation, bioenergetic homeostasis, complement, inflammation, angiogenesis, and extracellular matrix metabolism contribute to AMD pathogenesis over the disease course. To date, increasing genetic susceptibility loci have been identified, of which the most important ones are in the CFH and ARMS2 genes. The interplay between genetic factors and environmental factors has been gradually elucidated through new findings and the advent of new technologies. Based on the mechanistic understanding, slowing down the dry AMD progression by dietary antioxidants and zinc and preventing vision loss in patients with wet AMD by intravitreal anti-VEGF therapy have been achieved. However, it must be admitted that there is no cure for AMD yet. In this chapter, we are introducing the proven therapies for AMD patients at different stages and discussing some experimental therapies used in the real world clinical practice.
The field of robotics is a quickly evolving feat of technology that accepts contributions from various genres of science. Neuroscience, Physiology, Chemistry, Material science, Computer science, and the wide umbrella of mechatronics have all simultaneously contributed to many innovations in the prosthetic applications of robotics. This review begins with a discussion of the scope of the term robotic prosthetics and discusses the evolving domain of Neuroprosthetics. The discussion is then constrained to focus on various actuation and control strategies for robotic prosthetic limbs. This review discusses various soft robotic actuators such as EAP, SMA, FFA, etc., and the merits of such actuators over conventional hard robotic actuators. Options in control strategies for robotic prosthetics, that are in various states of research and development, are reviewed. This paper concludes the discussion with an analysis regarding the prospective direction in which this field of robotic prosthetics is evolving in terms of actuation, control, and other features relevant to artificial limbs. This paper intends to review some of the emerging research and development trends in the field of robotic prosthetics and summarize many tangents that are represented under this broad domain in an approachable manner.
Age-related macular degeneration (AMD) is one of the main causes of visual impairment and severe visual loss, and can progress to two advanced forms—neovascularization and atrophic. The field of anti-AMD drugs has undergone huge developments in recent years, from single-target intravitreal administration to current clinical studies with multi-target and non-invasive agents, offering interesting new pharmacological opportunities for the treatment of this disease. Hence, we summarize some of the approved anti-vascular endothelial growth factor (VEGF) drugs for neovascular AMD, especially their structural characteristics, clinical manifestations, dosing regimens, and safety issues of the anti-VEGF drugs highlighted. In addition, advances in atrophic AMD drug research are also briefly described.
Visual prostheses serve to restore visual function following acquired blindness. Acquired blindness (as opposed to congenital blindness) has many causes, including diseases such as retinitis pigmentosa, glaucoma, and macular degeneration, or trauma such as caused by automobile accident or blast damage from explosions. Many of the blindness-causing diseases target the retina or other ocular structure. Often, despite the loss of sensitivity to light, the remainder of the visual pathway is still functional, enabling electrical devices to deliver effective and meaningful visual information to the brain via arrays of electrodes. These arrays can be placed in any part of the early visual pathway, such as the retina, optic nerve, lateral geniculate nucleus, or visual cortex. A camera or other imaging source is used to drive electrical stimulation of remaining healthy cells or structures to create artificial vision and provide restoration of function. In this review, each approach to visual prostheses is described, including advantages and disadvantages as well as assessments of the current state of the art. Most of the work to-date has been targeting stimulation of (a) the retina, with three devices approved for general use and two more in clinical testing; (b) the lateral geniculate nucleus, with efforts still in the pre-clinical stage; and (c) the cortex, with three devices in clinical testing and none currently approved for general use despite the longest history of investigation of the three major approaches. Each class of device has different medical indications, and different levels of invasiveness required for implantation. All contemporary devices deliver relatively poor vision. There has been remarkable progress since the first proof-of-concept demonstration that used stimulation of the primary visual cortex, with the field exploring all viable options for restoration of function. Much of the progress has been recent, driven by advances in microelectronics and biocompatibility. With three devices currently approved for general use in various parts of the world, and a handful of additional devices well along in the pipeline toward approval, prospects for wide deployment of a device-based therapy to treat acquired blindness are good.
Vascular endothelial growth factor (VEGF)-A is differentially spliced to give two functionally different isoform families; pro-angiogenic, pro-permeability VEGF-Axxx and anti-angiogenic, anti-permeability VEGF-Axxxb. VEGF-A splicing is dysregulated in several pathologies, including cancer, diabetes, and peripheral arterial disease. The bichromatic VEGF-A splicing-sensitive fluorescent reporter harboured in a transgenic mouse is a novel approach to investigate the splicing patterns of VEGF-A in vivo. We generated a transgenic mouse harbouring a splicing-sensitive fluorescent reporter designed to mimic VEGF-A terminal exon splicing (VEGF8ab) by insertion into the ROSA26 genomic locus. dsRED expression denotes proximal splice site selection (VEGF-Axxx) and eGFP expression denotes distal splice site selection (VEGF-Axxxb). We investigated the tissue-specific expression patterns in the eye, skeletal muscle, cardiac muscle, kidney, and pancreas, and determined whether the splicing pattern could be manipulated in the same manner as endogenous VEGF-A by treatment with the SRPK1 inhibitor SPHINX 31. We confirmed expression of both dsRED and eGFP in the eye, skeletal muscle, cardiac muscle, kidney, and pancreas, with the highest expression of both fluorescent proteins observed in the exocrine pancreas. The ratio of dsRED and eGFP matched that of endogenous VEGF-Axxx and VEGF-Axxxb. Treatment of the VEGF8ab mice with SPHINX 31 increased the mRNA and protein eGFP/dsRED ratio in the exocrine pancreas, mimicking endogenous VEGF-A splicing. The VEGF-A exon 8 splicing-sensitive fluorescent reporter mouse is a novel tool to assess splicing regulation in the individual cell-types and tissues, which provides a useful screening process for potentially therapeutic splicing regulatory compounds in vivo
Emerging anti-vascular endothelial growth factor (anti-VEGF) therapies for neovascular age-related macular degeneration (nAMD) have revolutionised medical retina practice and the management and eventual outcome of nAMD. Recent research has focused on evaluating and comparing the efficacy of the two most widely employed anti-VEGF agents, bevacizumab and ranibizumab; however, a subgroup of patients with nAMD demonstrates a suboptimal response to standard therapy. We have therefore conducted a review of pertinent studies published until August 2018 which have documented the clinical efficacy when switching to a different anti-VEGF. Evidence on baseline disease characteristics, injection frequency and disease outcome has been obtained for patients treated with ranibizumab 0.5 mg and/or bevacizumab 1.25 mg and were switched to aflibercept 2 mg. Our review identified 45 studies investigating switching to aflibercept. Our review showed a clear anatomical benefit after the switch in terms of central retinal thickness and pigment epithelium detachment characteristics, whereas the functional outcomes were variable. Remarkable heterogeneity was documented among the relevant studies with regard to several factors including the baseline characteristics of the cohorts, the non-response definition and previous treatment protocols. Larger prospective trials with appropriate control arms are therefore required to elucidate the potential benefit when switching between anti-VEGF agents in refractory nAMD.
Purpose:
Two similarly designed phase 3 trials (HAWK and HARRIER) compared brolucizumab, a single-chain antibody fragment that inhibits vascular endothelial growth factor-A, with aflibercept to treat neovascular age-related macular degeneration (nAMD).
Design:
Double-masked, multicenter, active-controlled, randomized trials.
Participants:
Patients (N = 1817) with untreated, active choroidal neovascularization due to age-related macular degeneration in the study eye.
Intervention:
Patients were randomized to intravitreal brolucizumab 3 mg (HAWK only) or 6 mg or aflibercept 2 mg. After loading with 3 monthly injections, brolucizumab-treated eyes received an injection every 12 weeks (q12w) and were interval adjusted to every 8 weeks (q8w) if disease activity was present; aflibercept-treated eyes received q8w dosing.
Main outcome measures:
The primary hypothesis was noninferiority in mean best-corrected visual acuity (BCVA) change from baseline to Week 48 (margin: 4 letters). Other key end points included the percentage of patients who maintained q12w dosing through Week 48 and anatomic outcomes.
Results:
At Week 48, each brolucizumab arm demonstrated noninferiority to aflibercept in BCVA change from baseline (least squares [LS] mean, +6.6 [6 mg] and +6.1 [3 mg] letters with brolucizumab vs. +6.8 letters with aflibercept [HAWK]; +6.9 [brolucizumab 6 mg] vs. +7.6 [aflibercept] letters [HARRIER]; P < 0.001 for each comparison). Greater than 50% of brolucizumab 6 mg-treated eyes were maintained on q12w dosing through Week 48 (56% [HAWK] and 51% [HARRIER]). At Week 16, after identical treatment exposure, fewer brolucizumab 6 mg-treated eyes had disease activity versus aflibercept in HAWK (24.0% vs. 34.5%; P = 0.001) and HARRIER (22.7% vs. 32.2%; P = 0.002). Greater central subfield thickness reductions from baseline to Week 48 were observed with brolucizumab 6 mg versus aflibercept in HAWK (LS mean -172.8 μm vs. -143.7 μm; P = 0.001) and HARRIER (LS mean -193.8 μm vs. -143.9 μm; P < 0.001). Anatomic retinal fluid outcomes favored brolucizumab over aflibercept. Overall, adverse event rates were generally similar with brolucizumab and aflibercept.
Conclusions:
Brolucizumab was noninferior to aflibercept in visual function at Week 48, and >50% of brolucizumab 6 mg-treated eyes were maintained on q12w dosing interval through Week 48. Anatomic outcomes favored brolucizumab over aflibercept. Overall safety with brolucizumab was similar to aflibercept (ClinicalTrials.gov; NCT02307682, NCT02434328).
Background
To evaluate the relative efficacy and safety of anti-vascular endothelial growth factor (anti-VEGF) agents for the treatment of neovascular age-related macular degeneration (AMD). Methods
Systematic literature review identifying RCTs comparing anti-VEGF agents to another treatment published before June 2016. Efficacy assessed by mean change in best corrected visual acuity (BCVA) and central macular thickness (CMT) from baseline at up to 2 years followup. Safety assessed by proportions of patients with death, arteriothrombotic and venous thrombotic events, and at least one serious systemic adverse event at up to 2 years of followup. ResultsFifteen RCTs selected for meta-analysis (8320 patients). Two trials compared pegaptanib, and three trials compared ranibizumab versus control. Eight trials compared bevacizumab with ranibizumab. Two trials compared aflibercept with ranibizumab. There were no significant differences between bevacizumab and ranibizumab for BCVA at 1 or 2 years (weighted mean difference = − 0.57, 95% CI − 1.55 to 0.41, P = 0.25 and weighted mean difference = − 0.76, 95% CI − 2.25 to 0.73, P = 0.32, respectively). Ranibizumab was more effective in reducing CMT at 1 year (weighted mean difference = 4.49, 95% CI 1.13 to 7.84, P = 0.009). Risk ratios comparing rates of serious systemic adverse events at 1 and 2 years were slightly out of favour for bevacizumab. Aflibercept compared with ranibizumab demonstrated similar mean change in BCVA, reduction in CMT, and safety at 1 year. Conclusions
Bevacizumab and ranibizumab had equivalent efficacy for BCVA, while ranibizumab had greater reduction in CMT and less rate of serious systemic adverse events. Aflibercept and ranibizumab had comparable efficacy for BCVA and CMT. This provides information to balance comparable effects on vision and risk of adverse events between anti-VEGF agents.
Vascular endothelial growth factor-A (VEGF-A) is a key mediator of angiogenesis, signalling via the class IV tyrosine kinase receptor family of VEGF Receptors (VEGFRs). Although VEGF-A ligands bind to both VEGFR1 and VEGFR2, they primarily signal via VEGFR2 leading to endothelial cell proliferation, survival, migration and vascular permeability. Distinct VEGF-A isoforms result from alternative splicing of the Vegfa gene at exon 8, resulting in VEGFxxxa or VEGFxxxb isoforms. Alternative splicing events at exons 5–7, in addition to recently identified posttranslational read-through events, produce VEGF-A isoforms that differ in their bioavailability and interaction with the co-receptor Neuropilin-1. This review explores the molecular pharmacology of VEGF-A isoforms at VEGFR2 in respect to ligand binding and downstream signalling. To understand how VEGF-A isoforms have distinct signalling despite similar affinities for VEGFR2, this review re-evaluates the typical classification of these isoforms relative to the prototypical, “pro-angiogenic” VEGF165a. We also examine the molecular mechanisms underpinning the regulation of VEGF-A isoform signalling and the importance of interactions with other membrane and extracellular matrix proteins. As approved therapeutics targeting the VEGF-A/VEGFR signalling axis largely lack long-term efficacy, understanding these isoform-specific mechanisms could aid future drug discovery efforts targeting VEGF receptor pharmacology.
The introduction of anti-vascular endothelial growth factor (VEGF) agents such as ranibizumab and aflibercept has revolutionized the management of neovascular age-related macular degeneration. A number of randomized clinical trials have shown that ranibizumab and aflibercept produce similar efficacy and safety outcomes. Most of the switching studies published to date that show efficacy benefits are uncontrolled, retrospective trials with limitations in terms of their selection, monitoring, numbers, and assessment criteria. Based on the published literature to date, we propose arguments for and against switching anti-VEGF agents, provide our own perspective on this topic, and suggest a focus for future research.
Purpose
To evaluate the long-term results of limited macular translocation (LMT) surgery with radial chorioscleral outfolding in patients with wet age-related macular degeneration (AMD) and subfoveal choroidal neovascularization (CNV). In addition, to identify the factors associated with the final best-corrected visual acuity (BCVA).
Methods
The medical records of 20 eyes of 20 consecutive patients (65.2±9.8 years) who had undergone LMT for the treatment of wet AMD and were followed for at least 5 years, were reviewed. The surgical outcomes including the BCVA, degree of foveal displacement, and complications were recorded.
Results
The mean foveal displacement was 1332 ± 393 μm after the LMT. The CNV was removed in 16 eyes and photocoagulated in 4 eyes. The mean preoperative VA was 0.83 ± 0.33 logMAR units which significantly improved to 0.59 ± 0.37 logMAR units at 1 year after the surgery (P = 0.015). This BCVA was maintained at 0.59 ± 0.41 logMAR units on the final examination. The final BCVA was significantly correlated with that at 1 year after the surgery (r = 0.83, P<0.001). Multiple linear regression analysis showed that the final BCVA was significantly correlated with the BCVA at 1 year after the surgery (P<0.001), a recurrence of a CNV (P = 0.001), and the age (P = 0.022).
Conclusions
LMT improves the BCVA significantly at 1 year, and the improved BCVA lasted for at least 5 years. These results indicate that the impaired function of the sensory retina at the fovea can recover on the new RPE after the displacement for at least 5 years. The ability to maintain good retinal function on the new RPE for a long period is important for future treatments of CNVs such as the transplantation of RPE cells and stem cells.
The introduction of anti-vascular endothelial growth factor (anti-VEGF) has made significant impact on the reduction of the visual loss due to neovascular age-related macular degeneration (n-AMD). There are significant inter-individual differences in response to an anti-VEGF agent, made more complex by the availability of multiple anti-VEGF agents with different molecular configurations. The response to anti-VEGF therapy have been found to be dependent on a variety of factors including patient’s age, lesion characteristics, lesion duration, baseline visual acuity (VA) and the presence of particular genotype risk alleles. Furthermore, a proportion of eyes with n-AMD show a decline in acuity or morphology, despite therapy or require very frequent re-treatment. There is currently no consensus as to how to classify optimal response, or lack of it, with these therapies. There is, in particular, confusion over terms such as ‘responder status’ after treatment for n-AMD, ‘tachyphylaxis’ and ‘recalcitrant’ n-AMD. This document aims to provide a consensus on definition/categorisation of the response of n-AMD to anti-VEGF therapies and on the time points at which response to treatment should be determined. Primary response is best determined at 1 month following the last initiation dose, while maintained treatment (secondary) response is determined any time after the 4th visit. In a particular eye, secondary responses do not mirror and cannot be predicted from that in the primary phase. Morphological and functional responses to anti-VEGF treatments, do not necessarily correlate, and may be dissociated in an individual eye. Furthermore, there is a ceiling effect that can negate the currently used functional metrics such as >5 letters improvement when the baseline VA is good (ETDRS>70 letters). It is therefore important to use a combination of both the parameters in determining the response.The following are proposed definitions: optimal (good) response is defined as when there is resolution of fluid (intraretinal fluid; IRF, subretinal fluid; SRF and retinal thickening), and/or improvement of >5 letters, subject to the ceiling effect of good starting VA. Poor response is defined as <25% reduction from the baseline in the central retinal thickness (CRT), with persistent or new IRF, SRF or minimal or change in VA (that is, change in VA of 0+4 letters). Non-response is defined as an increase in fluid (IRF, SRF and CRT), or increasing haemorrhage compared with the baseline and/or loss of >5 letters compared with the baseline or best corrected vision subsequently. Poor or non-response to anti-VEGF may be due to clinical factors including suboptimal dosing than that required by a particular patient, increased dosing intervals, treatment initiation when disease is already at an advanced or chronic stage), cellular mechanisms, lesion type, genetic variation and potential tachyphylaxis); non-clinical factors including poor access to clinics or delayed appointments may also result in poor treatment outcomes. In eyes classified as good responders, treatment should be continued with the same agent when disease activity is present or reactivation occurs following temporary dose holding. In eyes that show partial response, treatment may be continued, although re-evaluation with further imaging may be required to exclude confounding factors. Where there is persistent, unchanging accumulated fluid following three consecutive injections at monthly intervals, treatment may be withheld temporarily, but recommenced with the same or alternative anti-VEGF if the fluid subsequently increases (lesion considered active). Poor or non-response to anti-VEGF treatments requires re-evaluation of diagnosis and if necessary switch to alternative therapies including other anti-VEGF agents and/or with photodynamic therapy (PDT). Idiopathic polypoidal choroidopathy may require treatment with PDT monotherapy or combination with anti-VEGF. A committee comprised of retinal specialists with experience of managing patients with n-AMD similar to that which developed the Royal College of Ophthalmologists Guidelines to Ranibizumab was assembled. Individual aspects of the guidelines were proposed by the committee lead (WMA) based on relevant reference to published evidence base following a search of Medline and circulated to all committee members for discussion before approval or modification. Each draft was modified according to feedback from committee members until unanimous approval was obtained in the final draft. A system for categorising the range of responsiveness of n-AMD lesions to anti-VEGF therapy is proposed. The proposal is based primarily on morphological criteria but functional criteria have been included. Recommendations have been made on when to consider discontinuation of therapy either because of success or futility. These guidelines should help clinical decision-making and may prevent over and/or undertreatment with anti-VEGF therapy.
To describe risk factors for geographic atrophy (GA) in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT).
Cohort within a randomized clinical trial.
We analyzed 1024 CATT patients with no GA visible on color fundus photographs (CFPs) and/or fluorescein angiograms (FAs) at enrollment.
Eyes were assigned to ranibizumab (0.5 mg) or bevacizumab (1.25 mg) treatment and to a 2-year monthly or pro re nata (PRN) injection regimen, or monthly injections for 1 year and PRN for 1 year. Demographic, genetic, and baseline ocular characteristics and lesion features of CFP/FA and optical coherence tomography (OCT) were evaluated as risk factors for GA through 2 years of follow-up. Time-dependent Cox proportional hazard models were used to estimate adjusted hazard ratios (aHRs).
Development of GA.
By 2 years, GA developed in 187 of 1024 patients (18.3%). Baseline risk factors for GA development included baseline visual acuity (VA) ≤20/200 (aHR, 2.65; 95% confidence interval [CI], 1.43-4.93), retinal angiomatous proliferation (RAP; aHR, 1.69; 95% CI, 1.16-2.47), GA in the fellow eye (aHR, 2.07; 95% CI, 1.40-3.08), and intraretinal fluid at the foveal center (aHR, 2.10; 95% CI, 1.34-3.31). Baseline factors associated with lower risk for GA development included blocked fluorescence (aHR, 0.49; 95% CI, 0.29-0.82), OCT measurements of subretinal fluid thickness of >25 μ (aHR, 0.52; 95% CI, 0.35-0.78), subretinal tissue complex thickness of >275 compared with ≤75 μ (aHR, 0.31; 95% CI, 0.19-0.50), and vitreomacular attachment (aHR, 0.55; 95% CI, 0.31-0.97). Ranibizumab compared with bevacizumab had a higher risk (aHR, 1.43; 95% CI, 1.06-1.93), and monthly dosing had a higher risk (aHR, 1.59; 95% CI, 1.17-2.16) than PRN dosing. There were no strong associations between development of GA and the presence of risk alleles for CFH, ARMS 2, HTRA1, C3, or TLR3.
Approximately one fifth of CATT patients developed GA within 2 years of treatment. Independent baseline risk factors included poor VA, RAP, foveal intraretinal fluid, monthly dosing, and treatment with ranibizumab. Anti-vascular endothelial growth factor therapy may have a role in the development of GA.
The authors have no proprietary or commercial interest in any of the materials discussed in this article.
Purpose:
Exudative AMD (wet AMD) is treated by monthly injection into the eye of anti-VEGF proteins. VEGF is alternatively spliced to produce numerous isoforms that differ in angiogenic activity. Serine-rich protein kinase-1 (SRPK1) has been identified as a regulator of pro-angiogenic VEGF splicing by phosphorylating serine-rich splicing factor-1 (SRSF1), which binds to VEGF pre-mRNA. We tested the hypothesis that topical (eye drop) SRPK1-selective inhibitors could be generated that reduce pro-angiogenic isoforms, and prevent choroidal neovascularization in vivo.
Methods:
Novel inhibitors were tested for SRPK inhibition in vitro, pro-angiogenic VEGF production in RPE cells by PCR and ELISA, and for inhibition of choroidal neovascularisation in mice and rats.
Results:
A novel disubstituted furan inhibitor was selective for the SRPK family of kinases and reduced expression of pro-angiogenic but not antiangiogenic VEGF isoforms. This inhibitor and previously identified SRPK inhibitors significantly reduced choroidal neovascularisation in vivo. Topical administration of SRPK inhibitors dose-dependently blocked CNV with an EC50 of 9 μM.
Conclusions:
These results indicate that novel SRPK1 selective inhibitors could be a potentially novel topical (eye drop) therapeutic for wet AMD.
In the treatment of neovascular age-related macular degeneration (AMD), vascular endothelial growth factor (VEGF) has emerged as a key target of therapy. Currently, patients with neovascular AMD are treated with monthly intravitreal injections of anti-VEGF medications. Aflibercept is a novel recombinant fusion protein engineered to bind all isoforms of VEGF-A, VEGF-B, and placental growth factor. It is the latest medication to receive US Federal Drug Administration (FDA) approval for the treatment of neovascular AMD. Theoretical models suggest this molecule may have a longer duration of action compared with current treatments. The results of the VEGF Trap-Eye: Investigation of Efficacy and Safety in wet Age-related Macular Degeneration studies (VIEW 1 and VIEW 2) support this by demonstrating that aflibercept, dosed every 2 months after a monthly loading dose for 3 months, was noninferior in the proportion of patients who maintained or improved vision at 52 weeks compared with monthly injections of ranibizumab. These results were maintained over the 2 years of the studies. Aflibercept (Eylea; Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA and Bayer, Basel, Switzerland) was approved by the FDA for the treatment of neovascular AMD on 18 November 2011.
To evaluate the relationships between the amount and type of dietary fat and intermediate age-related macular degeneration (AMD).
Women aged 50 to 79 years with high and low lutein intake from 3 sites of the Women's Health Initiative Observational Study were recruited into the Carotenoids in Age-Related Eye Disease Study. Fat intake from 1994 through 1998 was estimated using food frequency questionnaires, and AMD was assessed photographically from 2001 through 2004.
Intakes of omega-6 and omega-3 polyunsaturated fatty acids, which were highly correlated (r = 0.8), were associated with approximately 2-fold higher prevalence of intermediate AMD in high vs low quintiles. However, monounsaturated fatty acid intake was associated with lower prevalence. Age interactions were often observed. In women younger than 75 years (n = 1325), total fat and saturated fatty acid intakes were associated with increased prevalence of AMD (multivariate adjusted odds ratios [95% confidence interval] for intermediate AMD, 1.7 [1.0-2.7] for quintile 5 vs quintile 1 for total fat [P = .10 for trend] and 1.6 [0.7-3.6] for saturated fatty acids [P = .23 for trend]). The associations were reversed in older women.
These results support a growing body of evidence suggesting that diets high in several types of fat may contribute to the risk of intermediate AMD and that diets high in monounsaturated fatty acids may be protective.
Angiogenesis is essential for tumor growth. Vascular endothelial growth factor (VEGF) is the most potent growth factor of tumor neovasculature, has been shown to be up-regulated in every tumor studied thus far, and is correlated with tumor stage and progression. To determine whether specific VEGF splice variants were differentially expressed in renal cell carcinomas, 18 polar tumor samples were analyzed by reverse transcription-PCR using primers designed to differentiate between VEGF splice variants. Control tissue was derived from the opposite normal pole. An amplicon of length consistent with the previously described variant VEGF(148) was found in normal kidney tissue. Subsequent sequencing revealed a new VEGF isoform formed by differential splicing from the end of exon 7 into the 3' untranslated region of the mRNA. Cloning of this transcript showed that translation would result in a 165-amino acid peptide with an alternative terminal 6 amino acids, followed by a stop codon. We have termed this new isoform VEGF165b. This isoform was present in 17 of 18 normal kidney samples but only 4 of 18 cases from matched malignant tissue. VEGF165b was therefore expressed in a significantly higher proportion of normal tissue than malignant tissue from the same patients (P < 0.001). To determine the functional significance of this new isoform, we expressed the full-length protein in a heterologous expression system. Conditioned medium containing this isoform significantly and dose dependently inhibited VEGF165-mediated proliferation, migration of endothelial cells, and vasodilatation of mesenteric arteries. This novel isoform VEGF165b is therefore an endogenous inhibitory form of VEGF that is down-regulated in renal tumors and, therefore, may be anti-angiogenesis.
Vascular endothelial growth-factor receptors (VEGFRs) regulate the cardiovascular system. VEGFR1 is required for the recruitment of haematopoietic precursors and migration of monocytes and macrophages, whereas VEGFR2 and VEGFR3 are essential for the functions of vascular endothelial and lymphendothelial cells, respectively. Recent insights have shed light onto VEGFR signal transduction and the interplay between different VEGFRs and VEGF co-receptors in development, adult physiology and disease.
Ranibizumab--a recombinant, humanized, monoclonal antibody Fab that neutralizes all active forms of vascular endothelial growth factor A--has been evaluated for the treatment of neovascular age-related macular degeneration.
In this multicenter, 2-year, double-blind, sham-controlled study, we randomly assigned patients with age-related macular degeneration with either minimally classic or occult (with no classic lesions) choroidal neovascularization to receive 24 monthly intravitreal injections of ranibizumab (either 0.3 mg or 0.5 mg) or sham injections. The primary end point was the proportion of patients losing fewer than 15 letters from baseline visual acuity at 12 months.
We enrolled 716 patients in the study. At 12 months, 94.5% of the group given 0.3 mg of ranibizumab and 94.6% of those given 0.5 mg lost fewer than 15 letters, as compared with 62.2% of patients receiving sham injections (P<0.001 for both comparisons). Visual acuity improved by 15 or more letters in 24.8% of the 0.3-mg group and 33.8% of the 0.5-mg group, as compared with 5.0% of the sham-injection group (P<0.001 for both doses). Mean increases in visual acuity were 6.5 letters in the 0.3-mg group and 7.2 letters in the 0.5-mg group, as compared with a decrease of 10.4 letters in the sham-injection group (P<0.001 for both comparisons). The benefit in visual acuity was maintained at 24 months. During 24 months, presumed endophthalmitis was identified in five patients (1.0%) and serious uveitis in six patients (1.3%) given ranibizumab.
Intravitreal administration of ranibizumab for 2 years prevented vision loss and improved mean visual acuity, with low rates of serious adverse events, in patients with minimally classic or occult (with no classic lesions) choroidal neovascularization secondary to age-related macular degeneration. (ClinicalTrials.gov number, NCT00056836 [ClinicalTrials.gov].).
Because of the prevalence and devastating consequences of age-related macular degeneration (AMD), a systematic review devoted to low-vision rehabilitation and AMD seems timely and appropriate.
Several electronic databases were searched for studies from 1980 to 2006 involving individuals with low vision or visual impairment and rehabilitation interventions. Studies were assessed for quality and level of evidence.
The findings indicate that standard low-vision rehabilitation programs, conventional in-clinic assessments, and optical devices are effective ways of managing and living with vision loss. Areas of unmet need include determining which types of orientation and mobility programs and devices are most effective and developing methods of matching assistive technologies with the individual's visual and environmental requirements.
Additional randomized controlled trials with similar intervention comparisons and outcome measures are needed to form stronger conclusions for the most effective low-vision rehabilitation interventions for individuals with AMD.
Purpose
To evaluate the features and outcomes of eyes with retinal vasculitis and intraocular inflammation (IOI) after intravitreal injection (IVI) of brolucizumab 6mg/0.05ml for treatment of neovascular age-related macular degeneration (AMD).
Design
Retrospective case series.
Participants
Fifteen eyes from 12 patients identified from 10 centers in the United States.
Methods
Review of patient demographics, ophthalmologic examination and retinal imaging.
Main Outcome Measures
Baseline and follow-up visual acuity (VA), prior anti-vascular endothelial growth factor (VEGF) injections, clinical presentation, retinal findings, fluorescein angiography and treatment strategies
Results
The number of previous anti-VEGF IVIs ranged between 2 to 80 in the affected eye prior to the switch to brolucizumab. Retinal vasculitis and IOI were diagnosed at a mean of 30 days following brolucizumab IVI. Mean visual acuity prior to brolucizumab IVI was logMAR 0.426 (Snellen equivalent 20/53) and at diagnosis of retinal vasculitis was logMAR 0.981 (Snellen equivalent 20/191, range 20/25 to 20/1600) (P= 0.008). All affected eyes showed intraocular inflammation with variable combinations of focal or elongated segmental sheathing and discontinuity of small and large retinal arteries, sclerotic arteries, regions of vascular non-perfusion, cotton-wool spots, Kyrieleis plaques, irregular venous caliber with dilated and sclerotic segments, perivenular hemorrhages and foci of phlebitis. Fluorescein angiography revealed delayed retinal arterial filling, retinal vascular non-perfusion and variable dye leakage from affected vessels and the optic nerve. Systemic evaluation for embolic causes was unrevealing in 2 patients and 3 patients had negative evaluation for uveitis. Treatment consisted of various combinations of corticosteroids (systemic, intravitreal, topical) and two eyes had vitrectomy without improvement in vision. After mean follow-up of 25 days, mean visual acuity was logMAR 0.833 (Snellen equivalent 20/136), which was reduced compared to baseline (P=.033).
Conclusions
Retinal vasculitis and IOI after brolucizumab IVI is characterized by variable occlusion of large and /or small retinal arteries and perivenular abnormalities. It may span from peripheral vasculitis to occlusion of large retinal arteries around the optic nerve or macula with severe vision loss. A high index of suspicion is required as vitreous cells may obscure visualization of retinal details.
Purpose
To examine the clinical effects of switching intravitreal drug treatment from the approved vascular endothelial growth factor inhibitors, ranibizumab and aflibercept, to off label use of bevacizumab in patients with wet age-related macular degeneration.
Methods
This retrospective study scrutinized medical records of patients with wet age-related macular degeneration who switched therapy to bevacizumab due to a policy decision. Best corrected visual acuity, central retinal thickness, and number of injections before and 1 year after the switch was compared. The non-inferiority margin of best corrected visual acuity was five Early Treatment Diabetic Retinopathy Study letters.
Results
A switch from ranibizumab was evaluable in 93 eyes and from aflibercept in 19 eyes. Neither of the groups had a significant non-inferior visual acuity 16 month after the switch. Mean best corrected visual acuity in Early Treatment Diabetic Retinopathy Study letters was 63.8 (95% confidence interval: 61.3–66.4) before and 62.2 (95% confidence interval: 59.3–65.1) after in the ranibizumab group and 68.2 (95% confidence interval: 63.3–73.1) before and 67.7 (95% confidence interval: 62.8–72.6) after in the aflibercept group. Mean central retinal thickness in micrometers decreased from 254 (95% confidence interval: 247–261) to 250 (95% confidence interval: 225–275) in the ranibizumab group and from 265 (95% confidence interval: 255–276) to 262 (95% confidence interval: 251–273) in the aflibercept group. The treatment was changed again after the switch in 18% of the patients in the ranibizumab group and 19% in the aflibercept group and these subjects were excluded from the analyses.
Conclusion
In patients with neovascular age-related macular degeneration, a switch from ranibizumab or aflibercept to bevacizumab seems possible without a significant decrease in visual acuity in most patients.
Objective:
To evaluate associations of morphologic features with 5-year visual acuity (VA) in the Comparison of Age-related Macular Degeneration (AMD) Treatments Trials (CATT).
Design:
Cohort study within a randomized clinical trial.
Participants:
Participants in CATT.
Methods:
Eyes with AMD-associated choroidal neovascularization (CNV) and VA between 20/25 and 20/320 were eligible. Treatment was assigned randomly to ranibizumab or bevacizumab and to 3 dosing regimens for 2 years and was at the ophthalmologists' discretion thereafter.
Main outcome measures:
VA; thickness and morphological features on optical coherence tomography; lesion size and foveal composition on fundus photography and fluorescein angiography.
Results:
VA and image gradings were available for 523 of 914 (57%) participants alive at 5 years. At 5 years, 60% of eyes had intraretinal fluid (IRF), 38% had subretinal fluid (SRF), 36% had sub-retinal pigment epithelium (RPE) fluid, and 66% had subretinal hyper-reflective material (SHRM). Mean (SD) foveal center thickness (μm) was 148 (99) for retina, 5 (21) for SRF, 125 (107) for subretinal tissue complex, 11 (33) for SHRM, and 103 (95) for RPE+RPE elevation. SHRM, thinner retina, greater CNV lesion area and foveal center pathology (all p<0.001) and IRF (p<0.05), were independently associated with worse VA. Adjusted mean VA letters was 62 for no pathology in the foveal center, 61 for CNV, fluid, or hemorrhage, 65 for non-geographic atrophy (GA), 64 for non-fibrotic scar, 53 for GA, and 56 for fibrotic scar. Incidence or worsening of eight pathological features (foveal GA, foveal scar, foveal CNV, SHRM, foveal IRF, retinal thinning, CNV lesion area, and GA area) between years 2 and 5 were independently associated with greater loss of VA from year 2 to 5, and VA loss from baseline to year 5 .
Conclusions:
Associations between VA and morphologic features previously identified through year 1 were maintained or strengthened at year 5. New foveal scar, CNV, intraretinal fluid, SHRM and retinal thinning, development or worsening of foveal GA, and increased lesion size, are important contributers to the VA decline from year 2 to 5. A significant need to develop therapies to address these adverse pathological features remains.
Background:
Age-related macular degeneration (AMD) causes progressive and irreversible damage to the retina, resulting in loss of central vision. AMD is the third leading cause of irreversible visual impairment worldwide and the leading cause of blindness in industrialized countries. Since AMD is more common in older individuals, the number of affected individuals will increase significantly as the population ages. The implantable miniature telescope (IMT) is an ophthalmic device developed to improve vision in individuals who have lost vision due to AMD. Once implanted, the IMT is used to enlarge objects in the central visual field and focus them onto healthy areas of the retina not affected by AMD, allowing individuals to recognize objects that they otherwise could not see. It is unclear whether and how much the IMT can improve vision in individuals with end-stage AMD.
Objectives:
To assess the effectiveness and safety of the IMT in improving visual acuity and quality of life in people with late or advanced AMD.
Search methods:
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2017, Issue 11); Ovid MEDLINE; Embase.com; PubMed; LILACS; AMED; Web of Science Conference Proceedings Citation Index-Science; OpenSIGLE; the metaRegister of Controlled Trials (mRCT) (last searched 27 June 2014); ClinicalTrials.gov; the ICTRP and the US Food and Drug Administration (FDA) Medical Devices database. The date of the search was 2 November 2017, with the exception of mRCT which is no longer in service.
Selection criteria:
We planned to include randomized controlled trials (RCTs) and quasi-randomized trials that compared the IMT versus no IMT.
Data collection and analysis:
Two review authors independently assessed all studies for inclusion, using standard methodological procedures expected by Cochrane.
Main results:
Our search yielded 1042 unique records. We removed irrelevant studies after screening titles and abstracts, and evaluated five full-text reports from four studies; three were non-randomized studies. There was one ongoing RCT that compared the OriLens intraocular telescope with standard low vision training in eyes with end-stage AMD. Results for this study are expected in 2020.
Authors' conclusions:
We found no RCT or quasi-RCT and can draw no conclusion about the effectiveness and safety of the IMT in improving visual acuity in individuals with late or advanced AMD. Since the IMT is typically implanted monocularly based upon which eye has better best-corrected distance visual acuity, randomization between eyes within an individual may not be acceptable. Studies are needed that compare outcomes between individuals randomized to the device versus individuals not implanted, at least during study follow-up, who serve as controls.
The retinal pigment epithelium (RPE) is a highly specialized, unique epithelial cell that interacts with photoreceptors on its apical side and with Bruch's membrane and the choriocapillaris on its basal side. Due to vital functions that keep photoreceptors healthy, the RPE is essential for maintaining vision. With aging and the accumulated effects of environmental stresses, the RPE can become dysfunctional and die. This degeneration plays a central role in age-related macular degeneration (AMD) pathobiology, the leading cause of blindness among the elderly in western societies. Oxidative stress and inflammation have both physiological and potentially pathological roles in RPE degeneration. Given the central role of the RPE, this review will focus on the impact of oxidative stress and inflammation on the RPE with AMD pathobiology. Physiological sources of oxidative stress as well as unique sources from photo-oxidative stress, the phagocytosis of photoreceptor outer segments, and modifiable factors such as cigarette smoking and high fat diet ingestion that can convert oxidative stress into a pathological role, and the negative impact of impairing the cytoprotective roles of mitochondrial dynamics and the Nrf2 signaling system on RPE health in AMD will be discussed. Likewise, the response by the innate immune system to an inciting trigger, and the potential role of local RPE production of inflammation, as well as a potential role for damage by inflammation with chronicity if the inciting trigger is not neutralized, will be debated.
Vascular endothelial growth factor receptor (VEGFR) tyrosine kinases are key regulators of vascular development in vertebrates. Their activation is regulated through a family of secreted glycoproteins, the vascular endothelial growth factors (VEGFs). Expression, proteolytic processing, and diffusion range of VEGF proteins need to be tightly regulated, due to their crucial roles in development. While some VEGFs form concentration gradients across developing tissues and act as morphogenes, others function as inhibitors of receptor activation and downstream signaling. Ligand-induced receptor dimerization leads to activation of the intrinsic tyrosine kinase activity, which results in autophosphorylation of the receptors and in turn triggers the recruitment of interacting proteins as well as the initiation of downstream signaling. Although many biochemical details of VEGFR signaling have been revealed, the in vivo relevance of certain signaling aspects still remains to be demonstrated. Here, we highlight basic principles of VEGFR signaling and discuss its crucial role during development of the vascular system in mammals.
Angiogenesis is a complex biological phenomenon essential for a correct embryonic development and for post-natal growth. In adult life, it is a tightly regulated process but in several pathological conditions, angiogenesis results abnormal with either excessive or insufficient proliferation of blood vessels. The pro-angiogenic members of VEGF family, VEGF-A, VEGF-B and placental growth factor (PlGF), and the related receptors, VEGFR-1 and VEGFR-2, have a central and decisive role in pathological angiogenesis. Indeed, they are the targets for anti-angiogenic drugs currently approved: bevacizumab and ranibizumab, that specifically inhibit VEGF-A; aflibercept, that is able to prevent the activity of VEGF-A, VEGF-B and PlGF; several multirtarget tyrosine kinase inhibitors that are able to prevent VEGFR-1 and/or VEGFR-2 signaling. The anti-angiogenesis therapy has represented one of the most active fields of drug discovery of last decade and promises to be further expanded due the wide number of diseases for which it may by applied.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Objective
To describe the risk factors and associated population attributable risk for age-related maculopathy (ARM) and age-related macular degeneration(AMD) in Australians aged 40 years and older.
Methods
Residents were recruited from 9 randomly selected urban clusters and 4 randomly selected rural clusters in Victoria, Australia. At locally established test sites, the following information was collected: visual acuity, medical and health history, lifetime sunlight exposure, dietary intake, and fundus photographs. Age-related maculopathy and AMD were graded from the fundus photographs using an international classification and grading system. Backwards logistic regression was used to identify the independent risk factors for ARM and AMD.
Results
The participation rate was 83% (n = 3271) among the urban residents and 92% (n = 1473) among the rural residents. Gradable fundus photographs of either eye were available for 4345 (92%) of the 4744 participants. There were 656 cases of ARM, giving a weighted prevalence of 15.1% (95% confidence limit [CL], 13.8, 16.4); and there were 30 cases of AMD, giving a weighted prevalence of 0.69% (95% CL, 0.33, 1.03). In multiple logistic regression, the risk factors for AMD were as follows: age (odds ratio [OR], 1.23; 95% CL, 1.17, 1.29), smoked cigarettes for longer than 40 years (OR, 2.39; 95% CL, 1.02, 5.57), and ever taken angiotensin-converting enzyme inhibitors (OR, 3.26; 95% CL, 1.33, 8.01). The magnitude of all of these risk factors was slightly less for ARM, and having ever taken blood cholesterol–lowering medications was also significant (OR, 1.67; 95% CL, 1.12, 2.47; P = .001).
Conclusion
Smoking is the only modifiable risk factor for ARM and AMD, among the many environmental and systemic factors that were assessed.
Drugs that prevent the binding of VEGF to its trans-membrane cognate receptors have revolutionized the treatment of the most important chorioretinal vascular disorders: exudative age-related macular degeneration, diabetic macular edema, and retinal vein occlusions. Pegaptanib, which binds to VEGF165 and longer isoforms, ranibizumab and bevacizumab, which bind all VEGF-A isoforms, and aflibercept, which binds VEGF-A, VEGF-B, and placental growth factor, all bind VEGF165 with high affinity. The drugs have relatively long half-lives (7 to 10 days) after intravitreal depot injections and clinical durations of action that usually exceed 4 weeks. Plasma VEGF concentrations decrease after intravitreal injections of bevacizumab and aflibercept because their systemic half-lives are extended by their Fc fragments. Extensive in vitro and in vivo testing shows that the drugs prevent VEGF-mediated activation of endothelial cells while exhibiting little evidence of toxicity. Further anti-VEGF drug development is on-going.
To determine efficacy and safety of intravitreal aflibercept in patients with neovascular age-related macular degeneration (AMD) during a second year of variable dosing after a first-year fixed-dosing period.
Two randomized, double-masked, active-controlled, phase 3 trials.
Two thousand four hundred fifty-seven patients with neovascular AMD.
From baseline to week 52, patients received 0.5 mg intravitreal ranibizumab every 4 weeks (Rq4), 2 mg aflibercept every 4 weeks (2q4), 0.5 mg aflibercept every 4 weeks (0.5q4), or 2 mg aflibercept every 8 weeks (2q8) after 3 monthly injections. During weeks 52 through 96, patients received their original dosing assignment using an as-needed regimen with defined retreatment criteria and mandatory dosing at least every 12 weeks.
Proportion of eyes at week 96 that maintained best-corrected visual acuity (BCVA; lost <15 letters from baseline); change from baseline in BCVA.
Proportions of eyes maintaining BCVA across treatments were 94.4% to 96.1% at week 52 and 91.5% to 92.4% at week 96. Mean BCVA gains were 8.3 to 9.3 letters at week 52 and 6.6 to 7.9 letters at week 96. Proportions of eyes without retinal fluid decreased from week 52 (60.3% to 72.4%) to week 96 (44.6% to 54.4%), and more 2q4 eyes were without fluid at weeks 52 and 96 than Rq4 eyes (difference of 10.4% [95% confidence interval {CI}, 4.9-15.9] and 9.0% [95% CI, 3.0-15.1]). Patients received on average 16.5, 16.0, 16.2, and 11.2 injections over 96 weeks and 4.7, 4.1, 4.6, and 4.2 injections during weeks 52 through 96 in the Rq4, 2q4, 0.5q4, and 2q8 groups, respectively. The number of injections during weeks 52 through 96 was lower in the 2q4 and 2q8 groups versus the Rq4 group (differences of -0.64 [95% CI, -0.89 to -0.40] and -0.55 [95% CI, -0.79 to -0.30]; P < 0.0001, post hoc analysis). Incidences of Antiplatelet Trialists' Collaboration-defined arterial thromboembolic events were similar across group (2.4% to 3.8%) from baseline to week 96.
All aflibercept and ranibizumab group were equally effective in improving BCVA and preventing BCVA loss at 96 weeks. The 2q8 aflibercept group was similar to ranibizumab in visual acuity outcomes during 96 weeks, but with an average of 5 fewer injections. Small losses at 96 weeks in the visual and anatomic gains seen at 52 weeks in all arms were in the range of losses commonly observed with variable dosing.
Proprietary or commercial disclosure may be found after the references.
IMPORTANCE: Oral supplementation with the Age-Related Eye Disease Study (AREDS) formulation (antioxidant vitamins C and E, beta carotene, and zinc) has been shown to reduce the risk of progression to advanced age-related macular degeneration (AMD). Observational data suggest that increased dietary intake of lutein + zeaxanthin (carotenoids), omega-3 long-chain polyunsaturated fatty acids (docosahexaenoic acid [DHA] + eicosapentaenoic acid [EPA]), or both might further reduce this risk.
OBJECTIVES: To determine whether adding lutein + zeaxanthin, DHA + EPA, or both to the AREDS formulation decreases the risk of developing advanced AMD and to evaluate the effect of eliminating beta carotene, lowering zinc doses, or both in the AREDS formulation.
DESIGN, SETTING, AND PARTICIPANTS: The Age-Related Eye Disease Study 2 (AREDS2), a multicenter, randomized, double-masked, placebo-controlled phase 3 study with a 2 × 2 factorial design, conducted in 2006-2012 and enrolling 4203 participants aged 50 to 85 years at risk for progression to advanced AMD with bilateral large drusen or large drusen in 1 eye and advanced AMD in the fellow eye.
INTERVENTIONS: Participants were randomized to receive lutein (10 mg) + zeaxanthin (2 mg), DHA (350 mg) + EPA (650 mg), lutein + zeaxanthin and DHA + EPA, or placebo. All participants were also asked to take the original AREDS formulation or accept a secondary randomization to 4 variations of the AREDS formulation, including elimination of beta carotene, lowering of zinc dose, or both.
MAIN OUTCOMES AND MEASURES: Development of advanced AMD. The unit of analyses used was by eye.
RESULTS: Median follow-up was 5 years, with 1940 study eyes (1608 participants) progressing to advanced AMD. Kaplan-Meier probabilities of progression to advanced AMD by 5 years were 31% (493 eyes [406 participants]) for placebo, 29% (468 eyes [399 participants]) for lutein + zeaxanthin, 31% (507 eyes [416 participants]) for DHA + EPA, and 30% (472 eyes [387 participants]) for lutein + zeaxanthin and DHA + EPA. Comparison with placebo in the primary analyses demonstrated no statistically significant reduction in progression to advanced AMD (hazard ratio [HR], 0.90 [98.7% CI, 0.76-1.07]; P = .12 for lutein + zeaxanthin; 0.97 [98.7% CI, 0.82-1.16]; P = .70 for DHA + EPA; 0.89 [98.7% CI, 0.75-1.06]; P = .10 for lutein + zeaxanthin and DHA + EPA). There was no apparent effect of beta carotene elimination or lower-dose zinc on progression to advanced AMD. More lung cancers were noted in the beta carotene vs no beta carotene group (23 [2.0%] vs 11 [0.9%], nominal P = .04), mostly in former smokers.
CONCLUSIONS AND RELEVANCE: Addition of lutein + zeaxanthin, DHA + EPA, or both to the AREDS formulation in primary analyses did not further reduce risk of progression to advanced AMD. However, because of potential increased incidence of lung cancer in former smokers, lutein + zeaxanthin could be an appropriate carotenoid substitute in the AREDS formulation.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00345176.
PMID: 23644932
Objective:
Two similarly designed, phase-3 studies (VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD [VIEW 1, VIEW 2]) of neovascular age-related macular degeneration (AMD) compared monthly and every-2-month dosing of intravitreal aflibercept injection (VEGF Trap-Eye; Regeneron, Tarrytown, NY, and Bayer HealthCare, Berlin, Germany) with monthly ranibizumab.
Design:
Double-masked, multicenter, parallel-group, active-controlled, randomized trials.
Participants:
Patients (n = 2419) with active, subfoveal, choroidal neovascularization (CNV) lesions (or juxtafoveal lesions with leakage affecting the fovea) secondary to AMD.
Intervention:
Patients were randomized to intravitreal aflibercept 0.5 mg monthly (0.5q4), 2 mg monthly (2q4), 2 mg every 2 months after 3 initial monthly doses (2q8), or ranibizumab 0.5 mg monthly (Rq4).
Main outcome measures:
The primary end point was noninferiority (margin of 10%) of the aflibercept regimens to ranibizumab in the proportion of patients maintaining vision at week 52 (losing <15 letters on Early Treatment Diabetic Retinopathy Study [ETDRS] chart). Other key end points included change in best-corrected visual acuity (BCVA) and anatomic measures.
Results:
All aflibercept groups were noninferior and clinically equivalent to monthly ranibizumab for the primary end point (the 2q4, 0.5q4, and 2q8 regimens were 95.1%, 95.9%, and 95.1%, respectively, for VIEW 1, and 95.6%, 96.3%, and 95.6%, respectively, for VIEW 2, whereas monthly ranibizumab was 94.4% in both studies). In a prespecified integrated analysis of the 2 studies, all aflibercept regimens were within 0.5 letters of the reference ranibizumab for mean change in BCVA; all aflibercept regimens also produced similar improvements in anatomic measures. Ocular and systemic adverse events were similar across treatment groups.
Conclusions:
Intravitreal aflibercept dosed monthly or every 2 months after 3 initial monthly doses produced similar efficacy and safety outcomes as monthly ranibizumab. These studies demonstrate that aflibercept is an effective treatment for AMD, with the every-2-month regimen offering the potential to reduce the risk from monthly intravitreal injections and the burden of monthly monitoring.
Financial disclosure(s):
Proprietary or commercial disclosure may be found after the references.
Age-related macular degeneration (AMD), a progressive condition that is untreatable in up to 90% of patients, is a leading cause of blindness in the elderly worldwide. The two forms of AMD, wet and dry, are classified based on the presence or absence of blood vessels that have disruptively invaded the retina, respectively. A detailed understanding of the molecular mechanisms underlying wet AMD has led to several robust FDA-approved therapies. In contrast, there are no approved treatments for dry AMD. In this review, we provide insight into the critical effector pathways mediating each form of the disease. A recurring theme that spans most aspects of AMD pathogenesis is defective immune modulation in the classically immune-privileged ocular haven. Interestingly, the latest advances in AMD research also highlight common molecular disease pathways with other neurodegenerative disorders. Finally, the therapeutic potential of intervening at known mechanistic steps of AMD pathogenesis is discussed.
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.
Multicenter, randomized clinical trial.
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.
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.
Mean change in visual acuity.
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).
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.
To assess the preference-based comparative effectiveness (human value gain) and the cost-utility (cost-effectiveness) of a telescope prosthesis (implantable miniature telescope) for the treatment of end-stage, age-related macular degeneration (AMD).
A value-based medicine, second-eye model, cost-utility analysis was performed to quantify the comparative effectiveness and cost-effectiveness of therapy with the telescope prosthesis.
Published, evidence-based data from the IMT002 Study Group clinical trial. Ophthalmic utilities were obtained from a validated cohort of >1000 patients with ocular diseases.
Comparative effectiveness data were converted from visual acuity to utility (value-based) format. The incremental costs (Medicare) of therapy versus no therapy were integrated with the value gain conferred by the telescope prosthesis to assess its average cost-utility. The incremental value gains and incremental costs of therapy referent to (1) a fellow eye cohort and (2) a fellow eye cohort of those who underwent intra-study cataract surgery were integrated in incremental cost-utility analyses. All value outcomes and costs were discounted at a 3% annual rate, as per the Panel on Cost-Effectiveness in Health and Medicine.
Comparative effectiveness was quantified using the (1) quality-adjusted life-year (QALY) gain and (2) percent human value gain (improvement in quality of life). The QALY gain was integrated with incremental costs into the cost-utility ratio ($/QALY, or US dollars expended per QALY gained).
The mean, discounted QALY gain associated with use of the telescope prosthesis over 12 years was 0.7577. When the QALY loss of 0.0004 attributable to the adverse events was factored into the model, the final QALY gain was 0.7573. This resulted in a 12.5% quality of life gain for the average patient during the 12 years of the model. The average cost-utility versus no therapy for use of the telescope prosthesis was $14389/QALY. The incremental cost-utility referent to control fellow eyes was $14063/QALY, whereas the incremental cost-utility referent to fellow eyes that underwent intra-study cataract surgery was $11805/QALY.
Therapy with the telescope prosthesis considerably improves quality of life and at the same time is cost-effective by conventional standards.
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.
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.
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.
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.).
The vascular endothelial growth factor (VEGF) family of proteins regulates blood flow, growth, and function in both normal physiology and disease processes. VEGF-A is alternatively spliced to form multiple isoforms, in two subfamilies, that have specific, novel functions. Alternative splicing of exons 5-7 of the VEGF gene generates forms with differing bioavailability and activities, whereas alternative splice-site selection in exon 8 generates proangiogenic, termed VEGF(xxx), or antiangiogenic proteins, termed VEGF(xxx)b. Despite its name, emerging roles for VEGF isoforms on cell types other than endothelium have now been identified. Although VEGF-A has conventionally been considered to be a family of proangiogenic, propermeability vasodilators, the identification of effects on nonendothelial cells, and the discovery of the antiangiogenic subfamily of splice isoforms, has added further complexity to their regulation of microvascular function. The distally spliced antiangiogenic isoforms are expressed in normal human tissue, but downregulated in angiogenic diseases, such as cancer and proliferative retinopathy, and in developmental pathologies, such as Denys Drash syndrome and preeclampsia. Here, we examine the molecular diversity of VEGF-A as a regulator of its biological activity and compare the role of the pro- and antiangiogenic VEGF-A splice isoforms in both normal and pathophysiological processes.
Angiogenesis is a hallmark of tumor development and metastasis and is now a validated target for cancer treatment. However, the survival benefits of antiangiogenic drugs have thus far been rather modest, stimulating interest in developing more effective ways to combine antiangiogenic drugs with established chemotherapies. This review discusses recent progress and emerging challenges in this field; interactions between antiangiogenic drugs and conventional chemotherapeutic agents are examined, and strategies for the optimization of combination therapies are discussed. Antiangiogenic drugs such as the anti-vascular endothelial growth factor antibody bevacizumab can induce a functional normalization of the tumor vasculature that is transient and can potentiate the activity of coadministered chemoradiotherapies. However, chronic angiogenesis inhibition typically reduces tumor uptake of coadministered chemotherapeutics, indicating a need to explore new approaches, including intermittent treatment schedules and provascular strategies to increase chemotherapeutic drug exposure. In cases where antiangiogenesis-induced tumor cell starvation augments the intrinsic cytotoxic effects of a conventional chemotherapeutic drug, combination therapy may increase antitumor activity despite a decrease in cytotoxic drug exposure. As new angiogenesis inhibitors enter the clinic, reliable surrogate markers are needed to monitor the progress of antiangiogenic therapies and to identify responsive patients. New targets for antiangiogenesis continue to be discovered, increasing the opportunities to interdict tumor angiogenesis and circumvent resistance mechanisms that may emerge with chronic use of these drugs.
To determine whether vascular endothelial growth factor and basic fibroblast growth factor, which may be critical mitogens for neovascularization, are present together in human retinal and choroidal neovascular membranes.
Light microscopic immunocytochemistry using antibodies against vascular endothelial growth factor, basic fibroblast growth factor, and several cellular "marker" proteins on frozen sections from three choroidal neovascular membranes from patients with age-related macular degeneration, seven surgically excised epiretinal membranes from patients with proliferative diabetic retinopathy, and six epiretinal membranes from patients with nonischemic proliferative retinopathies.
All three choroidal neovascular membranes and all seven epiretinal membranes stained positive for vascular endothelial growth factor. Two choroidal neovascular membranes and six of the epiretinal membranes were positive for basic fibroblast growth factor. The same cells were often positive for both antigens. None of the epiretinal membranes from patients with nonischemic proliferative retinopathies were positive for either growth factor. Many of the cells that demonstrated growth factors were glial cells, vascular endothelial cells, and retinal pigment epithelial cells.
Colocalization of two growth factors in the same cells of ocular neovascular membranes suggests that more than one growth factor may contribute to pathologic angiogenesis. Growth factors in neovascular tissues are not localized exclusively in the vascular endothelium. Because expression of some growth factors is stimulated by hypoxia, their localization within choroidal neovascular membranes suggests that hypoxia may be an etiologic factor for choroidal as well as for retinal neovascularization.
Three selected aspects of human zinc homeostasis and requirements are reviewed with special reference to studies undertaken by the author and his colleagues: 1) the implications for the calculation of physiologic requirements for zinc of the interrelationship between two key variables of zinc homeostasis, intestinal excretion of endogenous zinc and total absorbed zinc, are examined at levels of absorption below those necessary to meet physiologic requirements; 2) a method for deriving average dietary zinc requirements from zinc-stable isotope tracer/metabolic studies is illustrated with examples of studies being conducted in developing countries; and 3) the effect of reduction of high intakes of phytic acid on zinc bioavailability is examined with test meals prepared from low-phytic-acid maize or isohybrid wild-type control maize.
Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen in vitro and an angiogenic inducer in a variety of in vivo models. Hypoxia has been shown to be a major inducer of VEGF gene transcription. The tyrosine kinases Flt-1 (VEGFR-1) and Flk-1/KDR (VEGFR-2) are high-affinity VEGF receptors. The role of VEGF in developmental angiogenesis is emphasized by the finding that loss of a single VEGF allele results in defective vascularization and early embryonic lethality. VEGF is critical also for reproductive and bone angiogenesis. Substantial evidence also implicates VEGF as a mediator of pathological angiogenesis. In situ hybridization studies demonstrate expression of VEGF mRNA in the majority of human tumors. Anti-VEGF monoclonal antibodies and other VEGF inhibitors block the growth of several tumor cell lines in nude mice. Clinical trials with various VEGF inhibitors in a variety of malignancies are ongoing. Very recently, an anti-VEGF monoclonal antibody (bevacizumab; Avastin) has been approved by the Food and Drug Administration as a first-line treatment for metastatic colorectal cancer in combination with chemotherapy. Furthermore, VEGF is implicated in intraocular neovascularization associated with diabetic retinopathy and age-related macular degeneration.
Pegaptanib, an anti-vascular endothelial growth factor therapy, was evaluated in the treatment of neovascular age-related macular degeneration.
We conducted two concurrent, prospective, randomized, double-blind, multicenter, dose-ranging, controlled clinical trials using broad entry criteria. Intravitreous injection into one eye per patient of pegaptanib (at a dose of 0.3 mg, 1.0 mg, or 3.0 mg) or sham injections were administered every 6 weeks over a period of 48 weeks. The primary end point was the proportion of patients who had lost fewer than 15 letters of visual acuity at 54 weeks.
In the combined analysis of the primary end point (for a total of 1186 patients), efficacy was demonstrated, without a dose-response relationship, for all three doses of pegaptanib (P<0.001 for the comparison of 0.3 mg with sham injection; P<0.001 for the comparison of 1.0 mg with sham injection; and P=0.03 for the comparison of 3.0 mg with sham injection). In the group given pegaptanib at 0.3 mg, 70 percent of patients lost fewer than 15 letters of visual acuity, as compared with 55 percent among the controls (P<0.001). The risk of severe loss of visual acuity (loss of 30 letters or more) was reduced from 22 percent in the sham-injection group to 10 percent in the group receiving 0.3 mg of pegaptanib (P<0.001). More patients receiving pegaptanib (0.3 mg), as compared with sham injection, maintained their visual acuity or gained acuity (33 percent vs. 23 percent; P=0.003). As early as six weeks after beginning therapy with the study drug, and at all subsequent points, the mean visual acuity among patients receiving 0.3 mg of pegaptanib was better than in those receiving sham injections (P<0.002). Among the adverse events that occurred, endophthalmitis (in 1.3 percent of patients), traumatic injury to the lens (in 0.7 percent), and retinal detachment (in 0.6 percent) were the most serious and required vigilance. These events were associated with a severe loss of visual acuity in 0.1 percent of patients.
Pegaptanib appears to be an effective therapy for neovascular age-related macular degeneration. Its long-term safety is not known.
To determine whether intravitreal bevacizumab could improve optical coherence tomography and visual acuity outcomes in a patient with neovascular age-related macular degeneration who was responding poorly to pegaptanib therapy, an intravitreal injection of bevacizumab (1.0 mg) was given. Within 1 week, optical coherence tomography revealed resolution of the subretinal fluid, resulting in a normal-appearing macular contour. The improved macular appearance was maintained for at least 4 weeks, and visual acuity remained stable. No inflammation was observed. An intravitreal injection of bevacizumab may provide an effective, safe, and inexpensive option for patients with age-related macular degeneration who are losing vision secondary to macular neovascularization.
The aim of this review was to examine the evidence as to whether antioxidant vitamin or mineral supplements prevent the development of AMD or slow down its progression.
Randomised trials comparing antioxidant vitamin and/or mineral supplement to control were identified by systematic electronic searches (updated August 2007) and contact with investigators. Data were pooled after investigating clinical and statistical heterogeneity.
There was no evidence that antioxidant (vitamin E or beta-carotene) supplementation prevented AMD. A total of 23 099 people were randomised in three trials with treatment duration of 4-12 years; pooled risk ratio=1.03 (95% CI, 0.74-1.43). There was evidence that antioxidant (beta-carotene, vitamin C, and vitamin E) and zinc supplementation slowed down the progression to advanced AMD and visual acuity loss in people with signs of the disease (adjusted odds ratio=0.68, 95% CI, 0.53-0.87 and 0.77, 95% CI, 0.62-0.96, respectively). The majority of people were randomised in one trial (AREDS, 3640 people randomised). There were seven other small trials (total randomised 525).
Current evidence does not support the use of antioxidant vitamin supplements to prevent AMD. People with AMD, or early signs of the disease, may experience some benefit from taking supplements as used in the AREDS trial. Potential harms of high-dose antioxidant supplementation must be considered. These may include an increased risk of lung cancer in smokers (beta-carotene), heart failure in people with vascular disease or diabetes (vitamin E) and hospitalisation for genitourinary conditions (zinc).
The age-related eye disease study (AREDS)