Pharmacovigilance
in Intraocular Antiangiogenic Therapy
Marianne
L. Shahsuvaryan
Marianne
L. Shahsuvaryan, Department of Ophthalmology, Yerevan
State Medical University, Yerevan, Republic of Armenia
Correspondence to: Marianne L. Shahsuvaryan, Department of
Ophthalmology, Yerevan State Medical University, 7Ap, 1Entr, 26 Sayat-Nova
Avenue, Yerevan, 0001, Republic of Armenia
Email: mar_shah@hotmail.com
Telephone: +374-10523 468
Received: March 26,
2015
Revised: May 13, 2015
Accepted: May 18, 2015
Published online: June 1, 2015
ABSTRACT
Context: Currently several antiangiogenic
agents are being widely and successfully used for the treatment of eye diseases
like neovascular macular degeneration, retinal vein occlusion and diabetic
macular edema. The discovery of anti-VEGF (Vascular endothelial growth factor)
agents has revolutionized the treatment of these conditions. Ophthalmology has
witnessed an explosion in the number of intravitreal injections delivered to
patients over the past 10 years, driven in large part by the introduction and
rapid incorporation of therapy with anti-VEGF agents.
Objective: Taking into consideration that VEGF
plays an important role not only in the pathophysiology of several
sight-threatening retinal disorders such as age-related macular degeneration,
retinal vein occlusion, diabetic macular edema and proliferative diabetic
retinopathy, but also in the physiology of the eye, and that more data are
becoming available in intraocular antiangiogenic therapy, chemical compound-related ocular side
effects across multiple antiangiogenic agents should be analyzed critically.
Methods: A comprehensive literature search was
conducted on Medline, PubMed, and Google Scholar databases in February 2015.
Search temporal limits included articles published from 2005 to 2015 with the
purpose of providing the most recent evidence. Studies were queried using the
following keywords in various combinations: antiangiogenics in eye diseases,
intravitreal pharmacotherapy by anti-VEGF, adverse effects, potential ocular
hazards, bevacizumab, pegaptanib sodium, ranibizumab, aflibercept. The articles
of high or medium clinical relevance were selected for review.
Results: Almost uniformly all trial evaluating
ocular safety of antiangiogenic agents reveal the serious side effects
including geographic atrophy, pigment epithelial tear, ocular hemorrhage
despite the fact that the incidence is low. Ocular safety concern in
intraocular pharmacotherapy by anti-angiogenic agents has a strong body of
clinical evidence, resulting in plenty of peer reviewed clinical articles.
Conclusion: Currently available findings obviate
the need to raise awareness about chemical compound-related ocular side effects
in patients with eye diseases treated by antiangiogenic agents. Hopefully that
noninvasive therapeutic options will become available soon.
© 2015 ACT. All
rights reserved.
Key words: Pegaptanib sodium; Ranibizumab; Aflibercept;
Bevacizumab; Intravitreal injections; Ocular side effects.
Shahsuvaryan ML. Pharmacovigilance in Intraocular
Antiangiogenic Therapy. International
Journal of Ophthalmic Research 2015; 1(1): 5-10 Available from: URL:
http://www.ghrnet.org/index.php/ijor/article/view/1158
INTRODUCTION
Vascular endothelial growth factor (VEGF) plays an important role not
only in the pathophysiology of several light-threatening retinal disorders such
as age-related macular degeneration, retinal vein occlusion, diabetic macular
edema and proliferative diabetic retinopathy contributing to increased
permeability across both the blood-retinal and blood-brain barrier, but also in
physiology of the eye[1]. Within the posterior segment of the eye,
VEGF is produced by retinal pigment epithelial cells, neurons, glial cells,
endothelial cells, ganglion cells, Muller cells, and smooth muscle cells. VEGF
appears to be essential for development and maintenance of functionally
efficient retinal vasculature as well as for integrity of the retinal pigment
epithelium (RPE), Bruch¡¯s membrane and choroidal endothelial cells[2].
Research conducted by Saint-Geniez et al[3] revealed an
important role for endogenous VEGF in the maintenance and function of adult
retina neuronal cells. Although VEGF affects all cells within the retina, its
primary targets are vascular endothelial cells.
The discovery
of anti-VEGF agents has revolutionized the treatment of aforementioned retinal
diseases. Ophthalmology has witnessed an explosion in the number of
intravitreal injections delivered to patients over the past 10 years, driven in
large part by the introduction and rapid incorporation of therapy with
anti-VEGF agents.
The term
antiangiogenic therapy was born more than 35 years ago by J. Folkman, who
hypothesized that cancer may be treated by abolishing the nutrients and
oxygen-providing blood vessels[4] by agents that could block the
angiogenic cascade. Monoclonal antibodies against VEGF were first developed as
an intravenous treatment for metastatic colorectal cancer[5,6].
Consequently,
several antiangiogenics have been developed for the treatment of
sight-threatening retinal diseases, including neovascular age-related macular
degeneration, retinal vein occlusions and diabetic macular edema in diabetic
retinopathy.
There are 4
anti-VEGF agents that are either approved or in common use in ophthalmology,
namely pegaptanib (Macugen, Pfizer), ranibizumab (Lucentis, Novartis),
aflibercept or VEGF Trap-Eye (EYLEA, Bayer) and bevacizumab (Avastin, Roche).
Pegaptanib
Pegaptanib is a selective VEGF inhibitor, targeting only one isoform of
the VEGF molecule, leaving other isoforms unaffected[7]. In 2004,
pegaptanib (Macugen (Pfizer and OSI/Eyetech Pharmaceuticals, Inc.) was the
first anti-VEGF agent to receive FDA approval for the treatment of neovascular
age-related macular degeneration (AMD). The use of pegaptanib has declined with
the release of newer anti-VEGF agents, such as ranibizumab (Lucentis™,
Genentech, Inc., South San Francisco, CA, and Novartis Pharma AG, Basel,
Switzerland), aflibercept (VEGF-trap eye, Eylea™, Regeneron Pharmaceuticals,
Inc., and Bayer Pharma AG, Berlin, Germany) and bevacizumab (Avastin™, Genentech, Inc.,
South San Francisco, CA, and Roche, Basel, Switzerland).
Ranibizumab
Ranibizumab (Lucentis™; Genentech, South San Francisco, CA, USA) is a
humanised antigen binding fragment of a murine full length monoclonal antibody
directed against human vascular endothelial growth factor - VEGF A. Ranibizumab
binds all active isoforms of VEGF-A and is thus considered a non-selective
VEGF-A inhibitor[8].
Aflibercept
Aflibercept or VEGF Trap-Eye (EYLEA, Bayer) is a fully human fusion
protein, consisting of soluble VEGF receptors 1 and 2, that binds all forms of
VEGF-A along with the related Placental Growth Factor (PlGF). VEGF Trap-Eye is
a specific and highly potent blocker of these growth factors. Aflibercept acts
as a decoy receptor binding-free VEGF[9].
Bevacizumab
Bevacizumab (Avastin, Roche), is a full-length, humanized monoclonal
antibody directed against all the biologically active isoforms of vascular
endothelial growth factor (VEGF) ¨CA. Bevacizumab binds to the receptor-binding
domain of all VEGF-A isoforms[10].
Bevacizumab is
FDA-approved for the treatment of colorectal cancer. However, because the agent
costs substantially less per dose than ranibizumab, it has been widely used
off-label since 2004 to treat several retinal diseases.
Currently more
data are becoming available due to wide antiangiogenic agents use for the
treatment of eye diseases, and safety data review for intravitreal injection of
common anti-VEGF agents was conducted[11].
VEGF plays an
important role in adult homeostasis. It is essential for postnatal angiogenesis
and other non- angiogenic functions, such as the modulation of tissue repair
and organ regeneration, vascular homeostasis by regulating key vascular
proteins[12,13], and inflammation.
Taking into
consideration that VEGF plays an important role in the physiology of the eye,
ocular safety data across multiple antiangiogenic agents should be analyzed
critically and chemical compound-related ocular side effects will be
highlighted.
Chemical
compound-related ocular side effects
Clinically proved effects
Geographic
atrophy: Geographic atrophy (GA) occurs with natural history of AMD, which marks
progression of disease, but on the other hand according to the results of the
MARINA trial[14] and further in the CATT trial[15], it
was revealed that ranibizumab causes deterioration of vision in treated
patients. When ranibizumab and bevacizumab have been compared at two years[15]
researchers evidenced more prominent harmful effect on retinal pigment
epithelium cells in case of ranibizumab.
In the CATT
trial[15,16] it has been shown that frequency of geographic atrophy
was higher in monthly treated patients subgroup.
Evidences from clinical trials evaluating effectiveness of different
antiangiogenic agents-Ranibizumab and bevacizumab in AMD therapy suggest
significantly increased frequency of developing geographic atrophy in the range
of 20-29% of cases, specifically
20% in the CATT Trial[15], and 28% and 29% in IVAN and HARBOR
trials respectively[17-19].
Evaluating
impact of treatment schedude in CATT[15] and IVAN[17]
trials it has been demonstrated that monthly injections predispose to geographic atrophy comparing to
as-needed (pro re nata-PRN). The HARBOR trial asseccing the risk factors for
geographic atrophy[18,19] indicated that absence of subretinal fluid
in the study eye and atrophic changes in the fellow eye could serve as a
predictors for aforementioned complication.
The latest
findings by Sch¨¹tze et al[20] evidenced that in neovascular
AMD progressive RPE atrophy and GA developed in the majority of eyes treated by
ranibizumab over two years.
Retinal pigment
epithelial tear
Tears of the retinal pigment epithelium occur with natural history of
AMD associated with choroidal neovascularization, but at the same time could be
a consequence of thermal laser therapy, photodynamic therapy and intraocular
pharmacotherapy by antiangiogenics[21].
The general
consensus is that retinal pigment epithelium tear is the ocular side effect of
intraocular antiangiogenic pharmacotherapy and is not related with any specific
anti-VEGF drug[22-24].
The latest
findings by Leon et al[25] evidenced that in 40% of AMD cases
the RPE tears occurred within two years of anti-VEGF injections. In 86.6% of
cases the RPE tear was associated with pigment epithelial detachment (PED), and
in 46.6% the RPE tear occurred in the central area of the retina and involved
the fovea. In all cases visual acuity decreased at the end of the follow-up
period (24 weeks) independently of the type or the topographical location of
the lesion.
In conclusion,
though RPE tears can occur spontaneously with natural history alone, the risk
of RPE tears with antiangiogenic therapy is enhanced by preexisting large and
high pigment epithelial detachments.
Ocular
hemorrhage
Few studies have focused on ocular hemorrhage following the use of
intravitreal injections of antiangiogenic agents[26-30]. Based on
Ladas et al[26] findings subconjunctival hemorrhage has been
documentated approximately in 10%
of injections recipients, and was more common in patients simultaneously
receiving aspirin[26]. For
bevacizumab it has been documented a case of a massive choroidal
detachment/hemorrhage following intravitreal injection[27].
According to the reports of Karagiannis et al[28] and
Modarres et al[29] massive subretinal hemorrhage has been
evidenced after switching from bevacizumab to ranibizumab and only in
bevacizumab injections[28,29].
The latest
research conducted by Azar et al[30] also revealed that
macular hematoma may follow intravitreal anti-VEGF injection for exudative AMD
with large occult neovascularization, especially if a large RPE tear is found.
In contrast to earlier study[25] in authors¡¯ opinion the occurrence
does not seem to be linked to anticoagulation treatment or the presence of
vitreomacular traction.
The long-term
data from the randomized, double-blind study[31] evaluating the
effectiveness and safety profile of the latest anti-VEGF agent aflibercept in
treatment of macular edema secondary to central retinal vein occlusion (CRVO)
also evidenced that the most frequent ocular serious adverse event from
baseline to week 100 was vitreous hemorrhage.
Impact on
ocular blood flow
Anti-VEGF therapy may therefore have adverse effects on ocular blood
flow. Von Hanno et al[32] presented two cases of retinal
artery occlusion after intravitreal injection of bevacizumab (Avastin) and
ranibizumab (Lucentis) respectively and concluded that the therapeutic
principle may be associated with an increased risk of retinal arterial
occlusions.
Increased risk
of ocular blood flow disturbancies was noted specifically in case of
bevacizumab injections¨Cretinal venous occlusions[33], anterior
ischemic optic neuropathy[34,35] development or exacerbation of
ocular ischemic syndrome[36], decrease in retrobulbar blood flow[37].
Leung et al[38]
presented a series of three patients of the nearly 200 patients with CRVO who
suffered apparent macular infarction within weeks of intravitreal
administration of bevacizumab. The authors stated that this has not been
described in the natural history of the disease and is associated with poor
visual outcomes.
Few studies
have focused on macular ischemia, after intravitreal injection of anti-VEGF
agents[39,40].
In
Manousaridis and Talk[40] opinion worsening of macular ischemia in
the long term cannot be definitely excluded, particularly in eyes with
significant ischaemia at baseline and after repeated intraocular anti-VEGF
injections. The decision to offer prolonged anti-VEGF treatment in cases of
significant coexisting macular ischaemia should not be based only on
measurements of macular thickness; instead repeat fluorescein angiograms should
be performed.
For
bevacizumab in CRVO also it has been demonstrated that ischemic retinal injury
may be severe adverse vascular reaction[41].
In conclusion,
available findings demonstrated significant impact of antiangiogenics on ocular
blood flow.
Tractional
retinal detachment
Few studies have focused on the development or progression of
tractional retinal detachment after intravitreal injection of bevacizumab
before vitrectomy for advanced proliferative diabetic retinopathy[42-44].
It is
recognized that intravitreal injection of anti-VEGF agents should be used with
extreme caution in extensive neovascularization secondary to diabetic
retinopathy or retinal vein occlusion, and the patient should be followed
closely for the possible need for vitrectomy.
The general
consensus is that ocular complications are higher in patients treated by
anti-VEGF agents[11,45].
Impact on
long-term efficacy
Tachyphylaxis/tolerance
The worldwide use of intravitreal application of anti-vascular growth
factor and the realisation that regular applications over long periods of time
are necessary to maintain vision in these eyes, has revealed the problem of
tolerance/tachyphylaxy[46]. In 2008, two papers suggested for the
first time possible tachyphylaxis/tolerance with chronic ranibizumab[47]
and bevacizumab treatment[48]. Binder S.[46] recommended
different options to prevent tachyphylaxis/tolerance: (1) to increase the
dosage or shorten treatment intervals if tolerance has developed; (2) to pause
treatment if tachyphylaxis has occurred; (3) to combine drugs with different
modes of action; or (4) to switch to a similar drug with different properties
(bevacizumab and ranibizumab differ in molecular size, affinity and
absorption).
Experimentally
proved effects
Impact on
retinal pigment epithelium
Malik [49] in the experimental study evaluated the safety
profiles of antiangiogenics on human retinal pigment epithelium cells. The
researchers concluded that bevacizumab and ziv-aflibercept showed mild
mitochondrial toxicity at clinically relevant doses, in contrast to
ranibizumab.
Impact on
photoreceptors and choriocapillaris
Avci et al[50] obviated a significant increase in
apoptotic activity in rabbit photoreceptor cells after bevacizumab and
pegaptanib sodium injections.
Kurihara et
al[51,52] in the experimental study revealed an essential role
of VEGF-A in regulating choroid vasculature and cone photoreceptors,
responsible for central and color vision and evidenced that VEGF inhibition
causes damage and loss of endothelial cells of the choriocapillaries and severe
vision loss secondary to cone cell death in mice.
Sene et al[53]
also emphasized the critical role of chronic VEGF suppression as a cause of the
loss of prosurvival and neurotrophic capacities of VEGF ending by vision loss.
Multiple
experimental studies were conducted on rat[54], rabbit[55]
and primate eye[56] to evaluate bevacizumab impact on
choriocapillaris.
The general
consensus[54-57] is that intravitreal injection of bevacizumab
causes a loss of choriocapillaris endothelial fenestrations and therefore VEGF
is required for the maintenance of the choroidal homeostasis[57].
Impact on
ciliary body
The role of VEGF-A in ciliary body homeostasis was explored by Ford et
al[58] in the experimental study.
Authors
discovered that inhibiting anti-VEGF might have a harmful effect on the ciliary
body, as a tissue responsible for producing aqueous humor, by degeneration of
capillary beds, particularly fenestrated capillaries found in the ciliary body.
Sugimoto et al[55] reconfirmed by electron microscopy
decrease of endothelial cell
fenestrations in the choriocapillaris and ciliary body after intravitreal
injections of bevacizumab.
Conclusion
The discovery of anti-VEGF agents has revolutionized the treatment of
neovascular macular degeneration, retinal vein occlusion and diabetic macular
edema. Ophthalmology has witnessed an explosion in the number of intravitreal
injections delivered to patients over the past 10 years, driven by the
introduction and rapid incorporation of therapy with antiangiogenics. At the
same time taking into consideration that VEGF plays an important role not only
in the pathophysiology of several sight-threatening retinal disorders, but also
in the physiology of the eye, there is a growing body of evidences on ocular
side effects in intraocular antiangiogenic therapy. Currently available findings obviate the
need to raise awareness about
chemical compound-related ocular side effects in patients with eye
diseases treated by antiangiogenic agents. Hopefully that noninvasive
therapeutic options will become available soon.
CONFLICT OF INTERESTS
The author has no conflicts of interest to declare.
REFERENCES
1 Quaggin
SE.Turning a blind eye to anti-VEGF toxicities. J Clin Invest 2012; 122(11):
3849¨C3851. Published online 2012 Oct 24. doi:
10.1172/JCI65509 PMCID: PMC3498935
2. Homayouni
M.Vascular Endothelial Growth Factors and Their Inhibitors in Ocular
Neovascular Disorders. J Ophthalmic Vis Res. 2009; 4(2): 105¨C114.
3. Saint-Geniez
M, Maharaj ASR, Walshe TE, Tucker BA, Sekiyama E, Kurihara T, Darland DC, Young
MJ, D¡¯Amore P. Endogenous VEGF Is Required For Visual Function: Evidence for a
Survival Role on M¨¹ller Cells and Photoreceptors. PLoS ONE 2008; 3(11): e3554.
doi:10.1371/journal.pone.0003554
4. Stewart
MW. The expanding role of vascular endothelial growth factor
inhibitors in ophthalmology. Mayo Clinic Proceedings, January 1, 2012
5. Homsi
J, Daud AI. Spectrum of activity and mechanism of action of
VEGF/PDGF inhibitors. Cancer Control. 2007;14(3), 285¨C294
6. Los
M, Roodhart JM, Voest EE. Target practice: lessons from Phase III trials with
bevacizumab and vatalanib in the treatment of advanced colorectal cancer.
Oncologist 2007;12(4), 443¨C450
7. Singerman
LJ, Masonson H, Patel M, Adamis AP, Buggage R, Cunningham E, Goldbaum M, Katz B, Guyer D.Pegaptanib sodium for neovascular
age-related macular degeneration: third-year safety results of the VEGF
Inhibition Study in Ocular Neovascularisation (VISION) trial. Br J Ophthalmol
2008; 92(12):1606-11. doi: 10.1136/bjo.2007.132597.
Epub 2008 Jul 9.
8. Rosenfeld PJ, Schwartz SD,
Blumenkranz MS, Miller JW, Haller JA, Reimann JD.
Maximum tolerated dose of a humanized anti-vascular endothelial growth factor
antibody fragment for treating neovascular age-related macular degeneration.
Ophthalmology 2005; 112: 1048¨C62.
9. Pieramici
DJ, Rabena MD. Anti-VEGF therapy: comparison of current and future agents. Eye
2008;22;1330¨C36.
10. Ferrara
N, Hillan KJ, Nowotny W. Bevacizumab (Avastin), a humanized anti-VEGF monoclonal
antibody for cancer therapy. Biochem Biophys Res Commun.
2005;333:328¨C35.
11. Falavarjani
KJ, Nguyen QD. Adverse events and complications associated with intravitreal
injection of anti-VEGF agents: a review of literature. Eye 2013; 27(7): 787¨C94.
Published online 2013 May 31. doi:
10.1038/eye.2013.107 MCID: PMC3709385
12. Luo
J, Xiong Y, Han X, Lu Y.VEGF non-angiogenic functions in adult organ
homeostasis: therapeutic implications. J Mol Med (Berl) 2011;89(7):635-45.
doi: 10.1007/s00109-011-0739-1. Epub 2011 Mar 2
13. Guangqi
EG, Cao Y, Bhattacharya S, Dutta S, Wang E, Mukhopadhyay D. Endogenous vascular
endothelial growth factor-A (VEGF-A) maintains endothelial cell homeostasis by
regulating VEGF receptor-2 transcription. J Biol Chem 2012;287(5):3029-41.
doi: 10.1074/jbc.M111.293985. Epub 2011 Dec 13.
14. Rosenfeld
PJ, Shapiro H, Tuomi L, Webster M, Elledge J, Blodi. MARINA
and ANCHOR Study Groups. Characteristics of patients losing vision after
2 years od monthly dosing in the phase III ranibizumab
clinical trials. Ophthalmology 2011;118-523-30.
15. Comparison
of Age-related Macular Degeneration Treatments Trials (CATT) Research Group.
Martin DF, Maguire MG, Fine SL, Ying GS, Jaffe GJ, Grunwald JE, Toth C, Redford
M, Ferris FL., 3rd Ranibizumab and bevacizumab for treatment of neovascular
age-related macular degeneration: two-year results. Ophthalmology 2012;119(7):1388¨C98.
16. CATT
Research Group. Ranibizumab and Bevacizumab for neovascular
age-related macular degeneration. N Engl J Med 2011;364:1897¨C908.
17. IVAN Study Investigators. Chakravarthy U, Harding SP, Rogers CA, Downes SM, Lotery AJ,
Wordsworth S, Reeves BC. Ranibizumab versus bevacizumab to treat
neovascular age-related macular degeneration: one-year findings from the IVAN
randomized trial. Ophthalmology 2012;119(7):1399¨C1411.
18. Busbee
BG, Ho AC, Brown DM, Heier JS, Suñer IJ, Li Z, Rubio RG, Lai P; HARBOR Study
Group. Twelve-month efficacy and safety of 0.5 mg or 2.0 mg
ranibizumab in patients with subfoveal neovascular age-related macular
degeneration.Ophthalmology. 2013;120(5):1046-56.
doi: 10.1016/j.ophtha.2012.10.014. Epub 2013 Jan 23
19. Ho
AC, Busbee BG, Regillo CD, Wieland MR, Van Everen SA, Li Z, Rubio RG, Lai
P.HARBOR Study Group. Twenty-four-month efficacy and safety of 0.5 mg or 2.0 mg
ranibizumab in patients with subfoveal neovascular age-related macular
degeneration.Ophthalmology 2014;121(11):2181-92. doi: 10.1016/j.ophtha.2014.05.009. Epub 2014 Jul 9.
20. Sch¨¹tze
C, Wedl M, Baumann B, Pircher M, Hitzenberger CK, Schmidt-Erfurth U.
Progression of retinal pigment epithelial atrophy in antiangiogenic therapy of
neovascular age-related macular degeneration. Am J
Ophthalmol. 2015 Mar 10. pii:
S0002-9394(15)00109-9. doi: 10.1016/j.ajo.2015.02.020.
[Epub ahead of print]
21. Cunningham
ET Jr, Feiner L, Chung C, Tuomi L, Ehrlich JS. Incidence of
retinal pigment epithelial tears after intravitreal ranibizumab injection for
neovascular age-related macular degeneration. Ophthalmology 2011;118:2447-52.
22. Chang
LK, Flaxel CJ, Lauer AK, Sarraf D. RPE tears after pegaptanib treatment in
age-related macular degeneration. Retina. 2007;27:857¨C63.
23. Shaikh
S, Olson JC, Richmond PP. Retinal pigment epithelial tears after intravitreal
bevacizumab injection for exudative age-related macular degeneration. Indian J Ophthalmol. 2007;55:470¨C2.
24. Smith
BT, Kraus CL, Apte RS. Retinal pigment epithelial tears in
ranibizumab-treated eyes. Retina. 2009;29:335¨C9.
25. Leon
EP, Saviano S, Zanei A, Pastore MR, Guaglione E, Mangogna A, Tognetto
D.Spontaneous or secondary to intravitreal injections of anti-angiogenic agents
retinal pigment epithelial tears in age-related macular degeneration.Int J
Ophthalmol 2014;7(4):681-85.doi:10.3980/j.issn.2222-3959.2014.04.18
26. Ladas
ID, Karagiannis DA, Rouvas AA, Kotsolis AI, Liotsou A, Vergados I. Safety of
repeat intravitreal injections of bevacizumab versus ranibizumab: our
experience after 2,000 injections. Retina 2009;29
(3):313¨C38.
27. Brouzas
D, Koutsandrea C, Moschos M, Papadimitriou S, Ladas I, Apostolopoulos M.
Massive choroidal hemorrhage after intravitreal administration of bevacizumab
(Avastin) for AMD followed by contralateral sympathetic ophthalmia. Clin
Ophthalmol 2009;3:457¨C59.
28. Karagiannis
DA, Mitropoulos P, Ladas ID. Large subretinal haemorrhage
following change from intravitreal bevacizumab to ranibizumab.
Ophthalmologica 2009;223 (4):279¨C82.
29. Modarres
M, Naseripour M, Falavarjani KG, Nikeghbali A, Hashemi M, Parvaresh MM.
Intravitreal injection of 2.5 mg vs 1.25 mg bevacizumab (avastin) for treatment
of CNV associated with AMD. Retina 2009;29:319¨C324.
30. Azar
G, Mauget-Faÿsse M, Nyouma J, Cohen SY, Coscas F, Français-Maury C, Souied E,
Soubrane G. Occurrence of macular hematoma after ranibizumab treatment for
age-related macular degeneration.Eur J Ophthalmol 2015; 25(2): 163 - 167
DOI:10.5301/ejo.5000529
31. Heier
JS, Clark WL, Boyer DS, Brown DM, Vitti R, Berliner AJ, Kazmi H, Ma Y, Stemper B, Zeitz O,
Sandbrink R, Haller JA. Intravitreal aflibercept injection for macular edema
due to central retinal vein occlusion: two-year results from the COPERNICUS
study.Ophthalmology 2014; 121(7):1414 PMID 24679444
32. von
Hanno T, Kinge B, Fossen K.Retinal artery occlusion following intravitreal
anti-VEGF therapy. Acta Ophthalmol 2010;88(2):263-6.
33. Mansour
AM, Bynoe LA, Welch JC, Pesavento R, Mahendradas P, Ziemssen F, Pai SA. Retinal vascular events after intravitreal bevacizumab. Acta
Ophthalmol 2010;88 (7):730¨C5.
34. Ganssauge
M, Wilhelm H, Bartz-Schmidt KU, Aisenbrey S. Nonarteritic anterior ischemic
optic neuropathy (NA-AION) after intravitreal injection of bevacizumab
(Avastin) for treatment of angoid streaks in pseudoxanthoma elasticum. Graefes
Arch Clin Exp Ophthalmol 2009;247 (12):1707¨C10.
35. Hosseini
H, Razeghinejad MR. Anterior ischemic optic neuropathy after intravitreal
injection of bevacizumab. J Neuroophthalmol 2009;29
(2):160¨C1.
36. Huang
ZL, Lin KH, Lee YC, Sheu MM, Tsai RK. Acute vision loss after intravitreal
injection of bevacizumab (avastin) associated with ocular ischemic syndrome. Ophthalmologica. 2010;224
(2):86¨C89.
37. Mete
A, Saygili O, Mete A, Bayram M, Bekir N. Effects of
intravitreal bevacizumab (Avastin) therapy on retrobulbar blood flow parameters
in patients with neovascular age-related macular degeneration. J Clin
Ultrasound 2010;38(2):66¨C70.
38. Leung
LS, Silva RA, Blumenkranz MS, Flynn HW Jr, Sanislo SR. Macular infarction
following intravitreal bevacizumab for treatment of central retinal vein
occlusion. Ophthalmic Surg Lasers Imaging 2012;43:e73-9.
39. Papadopoulou
DN, Mendrinos E, Mangioris G, Donati G, Pournaras CJ. Intravitreal ranibizumab
may induce retinal arteriolar vasoconstriction in patients with neovascular
age-related macular degeneration. Ophthalmology 2009;116
(9):1755¨C61.
40. Manousaridis
K, Talks J. Macular ischaemia: a contraindication for anti-VEGF treatment in
retinal vascular disease? Br J Ophthalmol 2012;96(2):179-84.
41. Isola
V, Pece A, Massironi C, Reposi S, Dimastrogiovanni F. Accelerated ischemic
vascular retinopathy after intravitreally injected bevacizumab for central
retinal vein occlusion in elderly patients.Clin Ophthalmol 2013;7: 455 ¨C60.
42. Arevalo
JF, Maia M, Flynn HW, Jr, Saravia M, Avery RL, Wu L, Eid Farah M, Pieramici DJ,
Berrocal MH, Sanchez JG.Tractional retinal detachment following intravitreal
bevacizumab (Avastin) in patients with severe proliferative diabetic
retinopathy. Br J Ophthalmol 2008;92 (2):213¨C16.
43. Oshima
Y, Shima C, Wakabayashi T, Kusaka S, Shiraga F, Ohji M, Tano Y. Microincision
vitrectomy surgery and intravitreal bevacizumab as a surgical adjunct to treat
diabetic traction retinal detachment. Ophthalmology.
2009;116 (5):927¨C38.
44. Yeh
PT, Yang CM, Lin YC, Chen MS, Yang CH. Bevacizumab pretreatment in vitrectomy
with silicone oil for severe diabetic retinopathy. Retina 2009;29 (6):768¨C74.
45. Day
S, Acquah K, Mruthyunjaya P, Grossman DS, Lee PP, SloanFA. Ocular complications
after anti-vascular endothelial growth factor therapy in Medicare patients with
age-related macular degeneration. Am J Ophthalmol 2011; 152(2): 266¨C72. PMCID:
PMC3143287 NIHMSID: NIHMS303283
46. Binder
S.Loss of reactivity in intravitreal anti-VEGF therapy: tachyphylaxis or
tolerance? Br J Ophthalmol 2012;96:1-2.
47. Keane
PA, Liakopoulos S, Onhchin SC. Quantitative subanalysis of optical coherence
tomography after treatment with ranibizumab for neovascular age-related macular
degeneration. Invest Ophthalmol Vis Sci 2008;49:3115-20.
48. Schaal
S, Kaplan HJ, Tetzel TH. Is there tachyphylaxis to intravitreal anti-vascular
endothelial growth factor pharmacotherapy in age-related macular degeneration ? Ophthalmology 2008;115:2199-205.
49. Malik
D, Tarek M, Caceres del Carpio J, Ramirez C, Boyer D, Kenney MC, Kuppermann BD.
Safety profiles of anti-VEGF drugs: bevacizumab, ranibizumab, aflibercept and
ziv-aflibercept on human retinal pigment epithelium cells in culture. Br J
Ophthalmol 2014;98:i11-i16
doi:10.1136/bjophthalmol-2014-305302
50. Avci
B, Avci R, Inan UU, Kaderli B.Comparative evaluation of apoptotic activity in
photoreceptor cells after intravitreal injection of bevacizumab and pegaptanib
sodium in rabbits. Invest Ophthalmol Vis Sci 2009;50(7):3438-46.
doi: 10.1167/iovs.08-2871. Epub 2009 Feb 28.
51. Kurihara
T, Westenskow PD, Bravo S, Aguilar E, Friedlander M. Targeted deletion of Vegfa
in adult mice induces vision loss. J Clin Invest 2012;122(11):4213¨C4217.
52. Kurihara
T, Westenskow PD, Friedlander M.Hypoxia-inducible factor (HIF)/vascular
endothelial growth factor (VEGF) signaling in the retina. Adv Exp Med Biol 2014;801:275-81. doi: 10.1007/978-1-4614-3209-8_35.
53. Sene
A, Chin-Yee D, Apte RS. Seeing through VEGF: innate and
adaptive immunity in pathological angiogenesis in the eye. Trends Mol
Med 2015;21(1):43-51. doi:
10.1016/j.molmed.2014.10.005. Epub 2014 Nov 1.
54. Shimomura
Y, Hirata A, Ishikawa S, Okinami S.Changes in choriocapillaris fenestration of
rat eyes after intravitreal bevacizumab injection. Graefes Arch Clin Exp
Ophthalmol 2009; 247(8):1089-94. DOI: 10.1007/s00417-009-1054-1
55. Sugimoto
Y, Mochizuki H, Miyagi H, Kawamata S, Kiuchi Y. Histological findings of uveal
capillaries in rabbit eyes after multiple intravitreal injections of
bevacizumab. Curr Eye Res 2013;38(4):487-96. doi: 10.3109/02713683.2013.763990. Epub 2013 Feb 1.
56. Peters
S, Heiduschka P, Julien S, Ziemssen F, Fietz H, Bartz-Schmidt KU; T¨¹bingen
Bevacizumab Study Group, Schraermeyer U.Ultrastructural findings in the primate
eye after intravitreal injection of bevacizumab. Am J Ophthalmol 2007;143(6):995-1002. Epub 2007 Apr 23.
57. Marneros
AG, Fan J, Yokoyama Y, Gerber HP, Ferrara N, Crouch RK, Olsen BR.Vascular
endothelial growth factor expression in the retinal pigment epithelium is
essential for choriocapillaris development and visual function. Am J Pathology 2005; 167(5), 1451-59.
58. Ford
KM, Saint-Geniez M, Walshe TE, D'Amore PA. Expression and
role of VEGF--a in the ciliary body. Invest Ophthalmol Vis Sci 2012 7;53(12):7520-7. doi:
10.1167/iovs.12-10098.
Peer reviewer: Yoshihiko Usui,
Department of Ophthalmology, Tokyo Medical University Hospital, 6-7-1
Nishishinjuku, Shinjuku-ku, Tokyo, Japan 160-0023.
Refbacks
- There are currently no refbacks.