Ординатура / Офтальмология / Английские материалы / Retinal and Vitreoretinal Diseases and Surgery_Boyd, Cortez, Sabates_2010

10.Klaver CC, Wolfs RC, Assink JJ, et al. Genetic risk ofage-relatedmaculopathy:population-basedfamilial aggregation study. Arch Ophthalmol. 1998;116:16461651.

11.Seddon JM,Ajani UA, Mitchell BD. Familial aggregation of age-related maculopathy. Am J Ophthalmol. 1997;123:199-206.

12.Seddon JM, Cote J, Page WF, et al. The US twin study of age-related macular degeneration. Arch Ophthalmol. 2005;123:321-327.

13.Meyers SM, Greene T, Gutman FA. A twin study of age-related macular degeneration. Am J Ophthalmol 1995; 120:757-766.

14.Klein ML, Mauldin WM, Stoumbos VD. Heredity and age-related macular degeneration: observations in monozygotic twins. Arch Ophthalmol 1994; 112:932-937.

22.Edwards AO, Ritter R, III, Abel KJ, Manning A, Panhuysen C & Farrer LA. Complement factor H polymorphism and age-related macular degeneration. Science 2005; [E-pub ahead of print].

23.Klein RJ, Zeiss C & Chew EY et al. Complement factor H polymorphism in age-related macular degeneration. Science 2005; [E-pub ahead of print].

24.Hageman GS, Luthert PJ, Victor Chong NH, Johnson LV, Anderson DH & Mullins RF. An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch’s membraneinterfaceinagingandage-relatedmacular degeneration. Progr Retin Eye Res 2001; 20: 705−732

25.Johnson LV, Leitner WP, Staples MK & Anderson DH. Complement activation and inflammatory processes in drusen formation and age related macular degeneration. Exp Eye Res 2001; 73: 887−896.

netic influence on age-related maculopathy: a twin study. Ophthalmology 2002: 109:730-736.

16.Grizzard SW, Arnett D, Haag SL. Twin study of age-related macular degeneration. Ophthalm Epidemiol 2003: 10:315-322.

17.Kenealy SJ, Schmidt S, Agarwal A et al. Linkage analysis for age-related macular degeneration supports a gene on chromosome 10q26. Mol Vis 2004; 10:57-61.

18.Schick JH, Iyengar SK & Klein BE et al. A wholegenome screen of a quantitative trait of age-related maculopathy in sibships from the Beaver Dam Eye Study. Am J Hum Genet 2003; 72: 1412−1424.

19.Seddon JM, Santangelo SL, Book K, Chong S & Cote J. A genomewide scan for age-related macular degeneration provides evidence for linkage to several chromosomal regions. Am J Hum Genet 2003; 73: 780−790.

20.Abecasis GR, Yashar BM & Zhao Y et al. Agerelated macular degeneration: a high-resolution genome scan for susceptibility loci in a population enriched for late-stage disease. Am J Hum Genet 2004; 74: 482−494.

Lichtner P, Meitinger T, Weber BH. Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. Hum Mol Genet. 2005;14:3227–36.

27.Yang Z, Camp NJ, Sun H, Tong Z, Gibbs D, Cameron DJ, Chen H, Zhao Y, Pearson E, Li X, Chien J, Dewan A, Harmon J, Bernstein PS, Shridhar V, Zabriskie NA, Hoh J, Howes K, Zhang K. A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science. 2006;314:992–3.

28.Seddon JM, Francis PJ, George S, Schultz DW, Rosner B, Klein ML. Association of CFH Y402H and LOC387715 A69S with progression of agerelated macular degeneration. JAMA. 2007 Apr 25;297(16):1793-800.

29.Francis PJ, Hamon SC, Ott J, Weleber RG, Klein ML. Polymorphisms in C2, CFB and C3 are associated with progression to advanced age related macular degeneration associated with visual loss. J Med Genet. 2009 May;46(5):300-7. Epub 2008 Nov 17.

ment factor H varient increases the risk of agerelated macular degeneration. Science 2005; [E-pub ahead of print].

epithelium. Invest Ophthalmol Vis Sci 1977; 16:807814.

31.Bok D, Young RW. Phagocytic properties of the RPE. In: Zinn KM, Marmor MF, eds. The retinal pigment epithelium. Cambridge, Mass: Harvard University Press, 1979, p 148-174.

44.Ylä-Herttuala S, Rissanen TT, Vajanto I, Hartikainen J. Vascular endothelial growth factors: Biology and currentstatusofclinicalapplicationsincardiovascular medicine. J Am Coll Cardiol. 2007;49:1015-1026.

tor loss in age-related macular degeneration. Invest Ophthalmol Vis Sci 1996; 37: 1236-1249.

33.Kennedy CJ, Rakoczy PE, Constable IJ. Lipofuscin of the retinal pigment epithelium: a review. Eye 1995; 9:763-771.

34.Hogan MJ. Role of the retinal pigment epithelium in macular disease. Trans Am Acad Otolaryngol Ophthalmol 1972;76:64.

35.Ramrattan RS, van der Schaft TL, Mooy CM et al. Morphometric analysis of Bruch’s membrane, the choriocapillaris, the choroid in aging. Invest Ophthalmol Vis Sci 1994; 35: 2857-2864.

36.Sarks. SH. Aging and degeneration in the macular region - a clinicopathological study. Br J Ophthalmol 1976;60:324-41.

37.Pauleikhoff. D, Alex Harper. C, Marshall. J, Bird. A - Aging changes in Bruch’s membrane. Ophthalmology 1990;97:171-78.

38.Klein R, Klein R, Davis M, Magli Y, Segal P, Klein B,HubbardL.TheWisconsinagerelatedmaculopathy grading system. Ophthalmology. 1991;98:1128-1134.

39.Klein ML, Ferris III FL, Armstrong J, et al. AREDS Research Group. Retinal precursors and the development of geographic atrophy in age-related macular degeneration. Ophthalmology 2008;115:1026-1031.

40.Bressler NM, Bressler SB, Seddon JM, Gragoudas ES, Jacobson LP. Drusen characteristics in patients with exudative versus nonexudative age-related macular degeneration. Retina. 1988;8:109-114.

41.Sarks JP, Sarks SH, Killingsworth MC. Evolution of soft drusen in age-related macular degeneration. Eye. 1994;8(pt 3):269-283.

42.Holz FG, Wolfensberger TJ, Piguet B, et al. Bilateral macular drusen in agerelated macular degeneration: prognosis and risk factors. Ophthalmology. 1994;101:1522-1528.

43.Maharaj AS, Saint-Geniez M, Maldonado AE, D’Amore PA. Vascular endothelial growth factor localization in the adult. Am J Pathol. 2006;168:639-648.

the eye: Biochemical Mechanisms of action and implications for novel therapies. Ophthalmic Research 1997;29:354-362.

46.Tolentino MJ, Miller JW, Gragoudas ES, et al. Vascular endothelial growth factor is sufficient to produce iris neovascularization and neovascular glaucoma in a nonhuman primate. Arch Ophthalmol. 1996;114:964-970.

47.Tolentino MJ, Miller JW, Gragoudas ES, et al. Intravitreous injections of vascular endothelial growth factor produce retinal ischemia and microangiopathy in an adult primate. Ophthalmology. 1996;103:1820-1828.

48.Adamis AP, Shima DT, Tolentino MJ, et al. Inhibition of vascular endothelial growth factor prevents retinal ischemia-associated iris neovascularization in a nonhuman primate.Arch Ophthalmol. 1996;114:6671.

49.Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331:1480-1487.

50.Lopez PF, Sippy BD, Lambert HM, et al. Transdifferentiated retinal pigment epithelial cells are immunoreactive for vascular endothelial growth factor in surgically excised age-related macular degeneration-related choroidal neovascular membranes. Invest Ophthalmol Vis Sci. 1996;37:855-868.

51.Chappelow AV, Kaiser PK. Neovascular age-related macular degeneration: potential therapies. Drugs. 2008;68:1029-1036.

52.van Wijngaarden P, Qureshi SH. Inhibitors of vascular endothelial growth factor (VEGF) in the management of neovascular age-related macular degeneration: a review of current practice. Clin Exp Optom. 2008;91:427-437.

53.von Rückmann A, Fitzke FW, Bird AC. Fundus autofluorescence in age-related macular disease imaged with a laser scanning ophthalmoscope. Invest Ophthalmol Vis Sci 1997;38:478-486.

aging of retinal autofluorescence in patients with age-relatedmaculardegeneration.Retina1997;17:385- 389.

55.Holz FG, Bellmann C, Margaritidis, Otto TP, Völcker HE. Pattern of increased in vivo fundus autofluorescence in the junctional zone of geographic atrophy of the retinal pigment epithelium associated with age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 1999;237:145-152.

56.Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) and Verteporfin In Photodynamic Therapy (VIP) Study Groups. Photodynamic therapy of subfoveal choroidal neovascularization with verteporfin: fluorescein angiographic guidelines for evaluation and treatment -- TAP and VIP report no. 2. Arch Ophthalmol. 2003;121:1253-1268.

57.Treatment of Age-Related Macular Degeneration With Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trialsTAP report 1. Arch Ophthalmol. 1999;117:1329-1345

58.Verteporfin In Photodynamic Therapy Study Group. Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: two-year results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularizationVerteporfin In Photodynamic Therapy report 2. Am J Ophthalmol. 2001;131:541-560.

59.Baker KJ. Binding of sulfobromoophthalein (BSP) sodium and indocyanine green (ICG) by plasma _1-lipoproteins. Proc Soc Exp Biol Med. 1966;122:957¬963.

60.Destro M, Puliafito CA. Indocyanine green videoangiography of choroidal neovascularization. Ophthalmology. 1989 Jun;96(6):846-53.

61.Yannuzzi LA, Slakter JS, Sorensen JA, et al. Digital indocyanine videoangiography and choroidal neovascularization. Retina 1992;12:191-223.

Hanutsaha P, Spaide RF, Schwartz SG, Hirschfeld JM, Orlock DA. Classification of choroidal neovascularization by digital indocyanine green videoan- giography.Ophthalmology.1996Dec;103(12):2054-60.

63.Yannuzzi LA, Hope-Ross M, Slakter JS, Guyer DR, Sorenson JA, Ho AC, Sperber DE, Freund KB, Orlock DA. Analysis of vascularized pigment epithelial detachments using indocyanine green videoangiography. Retina. 1994;14(2):99-113.

64.Staurenghi G, Orzalesi N, La Capria A, Aschero M. Laser treatment of feeder vessels in subfoveal choroidal neovascular membranes: a revisitation using dynamic indocyanine green angiography. Ophthalmology. 1998 Dec;105(12):2297-305.

65.Spaide RF,Yannuzzi LA, Slakter JS, et al. Indocyanine green videoangiography of idiopathic polypoidal choroidal vasculopathy. Retina 1995;15:100-110.

66.Yannuzzi LA, Negrao S, Iida T, et al. Retinal angiomatous proliferation in age-related macular degeneration. Retina 2001;21: 416-434.

67.Guyer DR, Yannuzzi LA, Slakter JS, et al. Digital indocyaninegreenvideoangiographyofcentralserous chorioretinopathy. Arch Ophthalmol 1994;112:1057–62.

68.Piccolino FC, Borgia L, Zinicola E, et al. Indocyanine green angiographic findings in central serous chorioretinopathy. Eye 1995;9:324–32.

69.Yannuzzi LA, Slakter JS, Gross NE, Spaide RF, Costa DL, Huang SJ, Klancnik JM Jr, Aizman A. Indocyanine green angiography-guided photodynamic therapy for treatment of chronic central serous chorioretinopathy: a pilot study. Retina. 2003 Jun;23(3):288-98.

70.Jaffe GJ, Caprioli J. Optical coherence tomography to detect and manage retinal disease and glaucoma. Am J Ophthalmol. 2004;137:156-169.

71.Sayanagi K, Sharma S, Yamamoto T, Kaiser PK. Comparison of spectral-domain versus time-domain optical coherence tomography in management of age-related macular degeneration with ranibizumab. Ophthalmology. 2009 May;116(5):947-55. Epub 2009 Feb 20.

INTRODUCTION

Age related diseases like Alzheimer’s Disease and age-related macular degeneration (AMD) are, by definition, chronic late-onset disorders with peculiar histopathological and clinical hallmarks. However, drusen and retinal pigmentepithelium(RPE)hyper/hypopigmentation, markers of age related maculopathy, as well asAlzheimer’s neurofibrillary tangles, can be found to a lesser extent in aged normal subjects.1,2 Susceptibility to develop these forms of deviations from normal ageing depends on a growing amount of genetic and environmental risk factors.Any of these factors and related pathophysiological modifications but age, is now looked at as the possible target of future therapies of these diseases and in particular AMD.

Genetic susceptibility is fundamental: population-based studies implicate a familial component in the disease’s pathogenesis, as indicated by studies of twins.3 Due to the multifactorial nature of the disease, only recently several genome-wide linkage analyses and case-control studies have identified different AMD-related gene variants, including complement factor H (CFH) polymorphisms at chromosome 1q31, LOC387715 and HtrA serine peptidase 1 (HTRA1) promoter at chromosome 10q26.4,5 The strongest association with the risk for developing all stages of age-related macular degeneration has been demonstrated for the gene encoding CFH.6-9 CFH is a regulator of the complement system of innate immunity by inhibiting the activation of C3 to C3a and C3b and by inactivating existing C3b, interfering with the progression

of the entire complement cascade.10 Several sequence variations in the region of the gene of CFH show a strong association with AMD susceptibility.11 Particularly, the association with AMD development of the single nucleotide tyrosine-histidine polymorphism in which a neutral tyrosine is replaced by a positively charged histidine (Y402H-encodind CFH variant) has been now reported and replicated in multiple samples;12 individuals homozigous for the CFH Y402H polymorfism showed a 48% risk of developing late AMD by age 95 compared to 22% for non carriers beeing the potential causal factor in more than 50% of all AMD cases.13

Moreover, the association between AMD and HTRA1, LOC387715 and complement components 2 and 3 (C2, C3) variants, independent of the CFH polymorphism, have been recently described.5,14-17 Multiple environmental risk factors have been determined by case-controlled population studies: body mass index, smoking, sunlight exposure.18,19 The most important factor (associated with at least a 2-fold increased risk) seems to be cigarette smoking and a direct association between the risk of developing advanced age-related macular degeneration and the number of smoked cigarettes has been documented.20,21

The etiology and pathogenesis of AMD remain largely unclear and a complex interplay of these genetic and environmental factors is thought to exist; recent reports show that the combination of genetic risk (CFH polymorphism) and smoking can significantly exceed the sum of the independent risk factors.13,22 Diverse cellular processes have been implicated in AMD pathogenesis, including

oxidative stress, inflammation, altered cholesterol metabolism and/or impaired function of the RPE and local or systemic factors are involved in the disease evolution to the advanced atrophic or neovascular complications.23,24 Histopathological and biochemical evidences point the interest on mechanisms of hyper accumulation of oxidative byproducts and abnormal activation of the inflammatory cascade.25,26 The retina has a high oxygen consumption related to photoreceptor visual function and RPE activity under a continuous high exposure of light with a chronic oxidative damage to retinal and RPE cell structures and DNA.27 Products of cell components’ oxidation are constituents of drusen. Drusen are deposits of neutral lipids, with esterified and nonesterified cholesterol, carbohydrates, zinc, and at least 120 different proteins, including apolipoproteins (e.g., apoE, apoB) (Figure 1); hallmarks of oxidative stress are carboxyethyl pyrrole (CEP) adducts, oxidative protein modifications generated from docosahexaenoate (DHA)-containing lipids, and crosslinked species of proteins TIMP3 and vitronectin.28 A chronic inflammatory process with direct and bystander cell damage attributable to a complement-mediated attack exacerbating the effect of primitive pathogenic stimuli is supported by several observations. Proteins involved with inflammation (e.g., amyloid-b, immunoglobulin light chains, factor X, C5, and C5b complex) are normal constituents of drusen.29 Mononuclear phagocyte series cells and giant cells with internalized pigment clumps are present in atrophic lesions.30 Interestingly, in vitro findings have shown that the RPE cells under oxidative stress lose the ability to suppress complement activation on their surface and synthesize the proangiogenic mediator Vascular Endothelial Growth Factor

(VEGF), possibly unbalancing the normal equilibrium between the proangiogenic VEGF and the anti-angiogenic neurotrophic and neuroprotective effects of Pigment EpithelialDerived Factor (PEDF) (Figure 1)25.

VEGF is one of the soluble modulators of ocular angiogenesis and, like Platelet derived Growth Factor (PDGF), Fibroblast Growth Factors (FGFs) 1 and 2 and Trasforming Growth Factor beta, is not expressed at detectable levels in normal RPE. These factors have been described in choroidal neovascularization (CNV) in several cell types, such as neuroretinal cells, RPE cells, endothelial cells, macrophages and fibroblasts.31-33

Experimental and clinical studies have demonstrated VEGF as critical for promoting CNV. The VEGF is a family of several heparin binding glycoproteins: VEGF-A (after referred to as VEGF) is involved in many processes implicating angiogenesis both in normal and in pathologic conditions. VEGF exists as 4 splice variants with a different number of amino acids: VEGF121, VEGF165, VEGF189 and VEGF286 and in a proteolytic cleavage product: VEGF110.34 Among these, VEGF165 seems to be the most biologically active and the principal responsible for pathologic ocular neovascularization.35 Soluble factors are not the only players involved in ocular neovascularization, a highly complex process

modulated also by non soluble factors like extracellular matrix elements and intercellular adhesion molecules.

A compelling amount of research informations is every day shedding light on mechanisms of AMD early and late phases while new therapeutic strategies and new molecules with therapeutic potential in halting a step of the AMD degenerative process are investigated.

DRY AMD THERAPY

The Age Related Disease Study (AREDS) established that the dietary supplementation with antioxidant (vitamin C 500 mg, vitamin E 400IU, b-carotene 15 mg) and zinc (zinc, 80 mg, as zinc oxide and copper, 2 mg, as cupric oxide) can reduce the risk of developing advanced age-related macular degeneration by as much as 25% over 5 years in subjects with at least moderate risk of age-related macular degeneration. This was accompanied by a 19% reduction in the risk of moderate vision loss (three or more ETDRS lines) at 5 years. The visual benefit is greatest, and was statistically significant in people with late AMD in one eye and early AMD in the other. There is no benefit in patients with no signs of AMD or those with bilateral, advanced AMD. These high doses of zinc and anti-oxidants cannot be achieved from diet alone.36 Beta-carotene is not recommended for smokers as it has been shown to increase the risk of lung cancer.37

The protective role of lutein and its isomer zeaxantin as well as the intake of unsaturated fatty acid like docosahexaenoic acid (DHA) are still under evaluation.38,39

Pharmacogenetic studies are now evaluating interactions between genetic variants and treatment response. Klein et al. have shown a treatment interaction between the CFH Y402H genotype and supplementation with antioxidants plus zinc on 876 patients in the AREDS category 3 and 4 at high risk of developing advanced AMD. Moreover, an interaction was observed in the groups taking zinc vs the groups taking no zinc, but not in groups taking antioxidants compared with those taking no antioxidants. There were no significant treatment interactions observed with LOC387715/ARMS2.40 Joint effect of demographic environmental and six genetic variants has recently allowed the formulaton of a prediction model for progression of AMD above and beyond the ocular signs and the only significant interaction between genetic variants and treatment was found with CFH Y402H polymorphism.12

WET AMD TREATMENT OPTIONS

Angioocclusive therapies. Until 2000, thermal laser photocoagulation was used to obliterate neovascularization. Macular Photocoagulation Study Group demonstrated that laser reduces the risk of severe visual loss for eyes with symptomatic choroidal neovascular membrane at least 200 μm from the center of the Foveal Avascular Zone (FAZ). However, only 13-26% of patients with exudative neovascular AMD fit the criteria for argon laser treatment and those undergoing laser treatment experienced CNV persistence or recurrence in 50% of cases.41 Subfoveal treatment usually resulted in immediate, significant visual acuity loss related to RPE and retinal

damage.42 Recently, a Cochrane systematic review concluded that laser photocoagulation slows progression of neovascularization in non-subfoveal lesions compared with observation alone.43

Photodynamic therapy (PDT) with verteporfin, a lipophylic dye administred intravenously, was the first pharmacologic treatment for wet AMD to receive regulatory approval, becoming the standard of care for the treatment of neovascular AMD.44 Verteporfin PDT’s clinical efficacy and safety has been demonstrated in several, multi-center, doublemasked, randomized placebo-controlled clinical studies. In the two studies known as TAP investigation (Treatment of AMD with PDT), verteporfin treatment significantly prevented moderate vision loss in patients with predominantly classic lesions. At 12 months, 61% of the treated patients versus 38% of the placebo-treated patients lost less than 15 ETDRS letters of best corrected visual acuity. In the subgroup analyses, patients with purely occult lesions showed a nonstatistically significant trend toward benefit, and patients with minimally classic lesions did not show any benefit.45 According to guidelines for the management of CNV published by European Medicine Agency and US Food and Drug Administration, PDT is indicated for patients with predominantly classic lesions secondary to AMD (50% or more of the lesion consists of classical choroidal neovascularization). The mechanism of action of PDT is not fully understood. It is thought that verteporfin accumulates preferentially in the neovasculature because of the increased uptake of low density lipoproteins (LDL) and expression of LDL receptors, in rapidly proliferating cells46

and is activated by a non-termal laser resulting in generation of reactive oxygen species causing endothelial cell changes leading to the occlusion of choroidal neovessels.47 However, several clinical and research evidences have demonstrated a lack of selectivity resulting in transient occlusion of the normal choriocapillaris with fluorangiographic and indocyanin green angiography evidence of hypoperfusion. Histology has shown a damage of the normal choroidal endothelial cells and neovessels formation within the CNV after PDT possibly related to the increased expression of VEGF in PDT treated areas.48 Recurrence of CNV and loss of vision are experienced by many of the treated patients. Therefore still debated are the treatment regimen and the light dose (reduced and half fluence) to be adopted in order to reduce the hypoperfusion of the normal choroid and the reported damage to the endothelial cells of the choriocapillaris and RPE in order to obtain a truly selective damage to the CNV.49

Alternativeangioocclusivetherapiesinclude transpupillary thermotherapy,50 radiotherapy51 and feeder vessel treatment of AMD-related CNV.52

Anti-VEGFtherapies.Anti-VEGF therapies inhibit blood vessel growth and leakage of CNV. To this date, two molecules have been approved by Food and Drug Administration: an aptamer (pegaptanib sodium; Macugen, OSI/Pfizer) and an antibody fragment (ranibizumab; Lucentis, Genentech). These molecules prevent the interaction between VEGF and VEGF receptors (VEGF-R) binding VEGF itself with high selectivity (Figure 2).

Pegaptanib sodium is an RNA oligonucleotide aptamer. The molecule has been modified at 2 hydroxyle groups of its bases to render it less susceptible to hydrolysis and conjugated to a polyethylene glycol group to increase the half-life. Pegaptanib binds specifically to VEGF 165.53 Two fase II/III concurrent, prospective, randomized, multicenter, double-masked, sham-controlled, dose-ranging (0.3,1,3 mg) clinical trials, VEGF Inhibition Study in Ocular Neovascularization (VISION), were published in 2004.54 At 54 weeks, 70% of patients in the 0.3 mg group met the primary end point (losing fewer than 15 letters at ETDRS chart), 71% in the 1 mg group, 65% in 3 mg group and 55% in the sham group. The 0.3 mg administered every 6 weeks was chosen as the lowest

efficacious dose. On average, patients in all groups still lose vision, ranging from a loss of 6 letters in the 1.0 mg group to 15 letters in the control group. In subgroup analysis, pegaptanib was effective across all CNV types. These results were confirmed at the end of the second year of follow-up, in which mean Visual Acuity (VA) of patients mantained with 0.3 mg every 6 weeks remained stable.55 Systemic potential adverse events of anti-VEGF drugs (hypertension, proteinuria and peripheral thromboembolic events) didn’t occur with greater frequency in patients who received pegaptanib sodium, local adverse events were transient and attributed to the injection procedure, as confirmed at the end of the third year of follow-up.56