Abstract
Aim
To record ocular vascular events following injections of vascular endothelium growth factor (VEGF) antagonists.
Methods
Collaborative multicenter case series (48 cases), literature reviews (32 cases), and reports to the FDA (64 cases) of patients that had vascular occlusions during anti-VEGF therapy were collected and analyzed.
Results
A total of 144 cases of ocular vascular events were identified, with these diagnosed a median of 15 days after anti-VEGF injection. The majority of patients had pre-existing risk factors for cardiovascular events and nine patients had a prior history of glaucoma. Mean visual acuity dropped by 6.4 lines with severe visual loss after injection to NLP (five eyes), LP (six eyes), and HM (two eyes). The overall risk of ocular vascular events following a VEGF antagonist injection was 0.108% in the general population and 2.61% in the diabetic population. Mean retinal arterial constriction after intravitreal bevacizumab in 13 eyes was 21% (standard deviation = 27%), and mean retinal venous constriction was 8% (standard deviation = 30%).
Conclusion
Ocular vascular events are rare during anti-VEGF therapy, but can lead to severe visual loss and may be caused by a number of factors including the vasoconstrictor effect of the drug, a post-injection rise of intraocular pressure, patient stress as a result of the procedure, and the patient’s natural history of underlying ocular or systemic diseases. The diabetic population appears to have a tendency towards ocular vascular occlusions.
Introduction
Vascular endothelial growth factor (VEGF) has vasodilatory effects so is used by vascular surgeons to treat ischemic diseases,Citation1 and intravitreal VEGF antagonists are now being used by ophthalmologists to treat various ischemic retinal disorders.Citation2,Citation3 Several studies report that fluorescein angiographic findings are absent following the administration of intravitreal bevacizumab or ranibizumab.Citation4–Citation9 Preliminary case series reported by some researchers suggest the possibility of a temporal link between these injections and subsequent retinal vascular events.Citation10–Citation21 In the current study additional data that was contributed by various collaborators and supplemented by the literatureCitation22–Citation44 is presented to further analyze the possible relationship between anti-VEGF injections and ocular vascular accidents. Additionally, the current study provides information regarding the characterization of patients developing ocular vascular complications after intravitreal injections of anti-VEGF drugs.
Methods
The current study is a retrospective survey among members of the American Society of Retinal Specialists who were invited to contribute a detailed protocol of cases that had vascular occlusions (central retinal artery occlusion [CRAO], branch retinal artery occlusion [BRAO], capillary occlusion, central retinal vein occlusion [CRVO], branch retinal vein occlusion [BRVO], anterior ischemic optic neuropathy [AION], and ocular ischemic syndrome) following anti-VEGF therapy. This research was approved by the Institutional Research Board (Rafic Hariri University Hospital, an affiliate of the American University of Beirut). Each center received Ethical Committee approval for the use of anti-VEGF for specific use and data analyses. The data collected included risk factors for vascular occlusion (carotid disease, coronary artery disease, systemic hypertension, diabetes mellitus, migraine, smoking, and glaucoma), the intraocular pressure on discharge, and the time period from intravitreal injection to detection of the vascular event. The total number of injections per investigator was also recorded.
A 14-month prospective study was also performed at Mansoura University using intravitreal bevacizumab. This included 42 patients, 33 of whom had proliferative diabetic retinopathy, seven with age-related macular degeneration, and two with central retinal vein occlusion. The study was approved by the Ethical Committee of Mansoura University.
Additionally, all studies in the literature regarding treatments with ranibizumab, bevacizumab, pegaptanib, and aflibercept as listed in PubMed and Scopus prior to August 2011 were searched for reports of adverse effects. As well as this, detailed reports of adverse effects of anti-VEGF medications sent to the FDA prior to April 2011 were retrieved via patientsville.com (for reports submitted from 2006 to 2009) and eHealthme.com (for reports submitted from 2010 to 2011), and retinal vascular events were selected for the current study.
Digital fundus photography and computerized determination of retinal trunk vessel diameters were performed using the previously described software.Citation3,Citation45,Citation46 For each case the pre- and post-anti-VEGF treatment fundus photographs were analyzed using custom computer software. For each case a grader (PKK) chose at least two artery segments and two vein segments that were deemed the most suitable for analysis based on image quality, contrast, straightness of the vessel, absence of branching, and absence of vessel crossings. Images of these vessel segments taken before and after anti-VEGF treatment were analyzed for each case. Images were considered non-gradable if the image was of poor quality (low contrast), as judged by the grader. When necessary, images were calibrated by scaling them so that they were of equal size. Results were presented as the relative change in vessel diameter following anti-VEGF treatment.
Results
A total of 144 cases were available for this study, which included 32 cases retrieved from the literature, 64 reports to the Food and Drug Administration (FDA), and 48 cases contributed from 22 centers across Africa, America, Asia, and Europe ( and ). Eight of these cases were part of a prospective study at Mansoura University (Mansoura City, Egypt) of 42 patients treated with intravitreal bevacizumab (33 patients with advanced proliferative diabetic retinopathy, seven with choroidal neovascularization, and two with central retinal vein occlusion). From 1665 reports of adverse effects following treatment with ranibizumab, 7167 reports of adverse effects following treatment with bevacizumab, 355 reports of adverse effects following treatment with pegaptanib, and 74 reports of adverse effects following treatment with aflibercept (VEGF Trap), the current study collected data on twelve ranibizumab-, 28 bevacizumab-, and six pegaptanib-related retinal vascular events.
Table 1 Collaborative and literature review of 106 cases of ocular vascular complications of the VEGF antagonist bevacizumab: clinical profile
Table 2 Collaborative and literature review of 38 cases of ocular vascular complications of VEGF antagonists excluding bevacizumab (ranibizumab and pegaptanib): clinical profile
Overall, 30 received ranibizumab, 9 pegaptanib and 106 bevacizumab (of which 13 received systemic bevacizumab, one received intracameral bevacizumab, one received 0.625 mg intravitreal bevacizumab, six received 2.5 mg intravitreal bevacizumab, and 55 received 1.25 mg intravitreal bevacizumab). The patient’s gender was not always specified, but of those patients for whom this was specified there were 53 males and 55 females. In 95 patients, the median age was 67 (range = 0–95 years; mean = 64.5 years). Vascular events were diagnosed a median of 15 days after treatment (n = 56; range = 0–60 days). The median number of prior injections was one (range = 0–34). The right eye was involved in 30 patients, and the left eye in 28 patients (five patients had bilateral events, while the side was not specified for the remainder).
A majority of patients had preexisting risk factors for cardiovascular events. More specifically, diabetes mellitus was documented in a total of 44 patients. There were 37 diabetic patients in the combined group of 80 patients from the collaborative study and the literature review, ie, 46.3% of the combined group had diabetes mellitus. Other systemic disorders of the whole series included systemic hypertension in 31 patients, coronary heart disease in 16, and carotid artery disease in eight. Moreover, nine patients had a prior history of glaucoma. Mean initial intraocular pressure was 15.5 mm Hg (range = 7–24 mm Hg), and on discharge this was 21.5 mm Hg (range = 11–50 mm Hg) (n = 32). Paracentesis was performed in only three cases after the injection to reverse post-injection ocular hypertension and to facilitate retinal perfusion as assessed by indirect ophthalmoscopy (two eyes had neovascular glaucoma, and one eye had central retinal artery occlusion at a post-injection pressure of 21 mm Hg).
The major ocular conditions under therapy included diabetic retinopathy in 39 patients (21 with proliferative retinopathy and twelve with background retinopathy), wet age-related macular degeneration in 25, and retinal venous occlusion in 18 (13 central and five branch varieties). The ocular vascular events registered were ocular vascular occlusions (of an unspecified type in 30 cases), ipsilateral central retinal artery occlusion (19 cases), contralateral central retinal artery occlusion (one case), branch retinal artery occlusion (four cases), unspecified retinal artery occlusion (14 cases), ophthalmic artery occlusion (two cases), choroidal ischemia (one case), retinal capillary occlusion (31 cases, 19 of which were causing macular ischemia), central retinal vein occlusion (three cases), branch retinal vein occlusion (four cases), unspecified retinal vein occlusion (twelve cases), retinal artery spasm (two cases), anterior ischemic optic neuropathy (16 cases), ischemic optic neuropathy (four cases), and one case of vision loss of unspecified origin ( and ).
The median follow-up time in 48 patients was 3 months (average = 8 months; range = 1–36 months). Mean visual acuity (log Mar) dropped by 6.4 lines from 0.85 (20/142; median = 0.7) to 1.49 (20/618; median = 1.0) (Student’s t-test n = 62; P = 0.0002). 40 eyes lost vision, ten eyes maintained vision, and 15 eyes gained vision at the last carried examination. Severe visual loss after injection to no light perception (NLP) occurred in five eyes, light perception (LP) in six eyes, and hand motion (HM) in three eyes.
Ocular vascular events occurred during anti-VEGF therapy in eight of 42 of patients (19.0%) in this selective prospective study. Overall in 26 centers, 55 ocular vascular events were reported among a total of 51,152 patients (0.108%) that received intravitreal anti-VEGF therapy ( and ). Eight ocular vascular events were reported in five centers among a total of 5340 patients (0.149%) that received intravitreal bevacizumab therapy. In the subset of the population who were diabetic, 15 ocular vascular events were reported in four centers from a total of 575 patients (2.61%; and ). In one center, two cases of retinal vascular occlusions followed intravitreal VEGF antagonists from a total of 300 retinovascular occlusion cases examined. In a double blind randomized prospective study, two patients (2%) developed retinovascular events among 102 diabetics with macular edema treated with intravitreal ranibizumab, while there were no events reported in the control group.Citation30 Terui et alCitation37 described the occurrence of capillary nonperfusion in four out of 58 eyes (6.9%) with branch retinal vein occlusion 1 month after intravitreal bevacizumab (note that this was minimal in three eyes and marked in one); it is unknown if this is related to the injection or part of the natural history of the ocular disease.
Retinal vasoconstriction was observed after both bevacizumab and ranibizumab injections. More specifically, vasoconstriction analyses were available in 13 of the submitted 20 eyes (seven eyes did not meet the requirements for a paired comparison; ). Vasoconstriction was measured between 7 and 30 days (median = 14 days) after injection of bevacizumab (1.25 mg) in 13 eyes. Mean retinal arterial constriction was 21% (standard deviation = 27%) and mean venous constriction was 8% (standard deviation = 30%). Four cases had prominent retinal arterial vasoconstriction of 78%, 57%, 54%, and 28%, while a fifth eye had 33% retinal venous constriction. Vasoconstriction was also measured in one eye that had intravitreal ranibizumab (0.5 mg), with 42% retinal arterial constriction and 16% retinal venous constriction reported.
Table 3 Retinal vasoconstriction values in subjects with ocular vascular events during bevacizumab therapy in 13 eyes, and intravitreal ranibizumab therapy in one eye
Discussion
The adverse events associated with systemic bevacizumab include hypertension, proteinuria, and thromboembolism.Citation44,Citation47 Mourad et al used intravital video microscopy to measure dermal capillary densities in the dorsum of the fingers of patients receiving systemic bevacizumab and showed endothelial dysfunction and rarefaction by laser Doppler flowmetry.Citation48 The ocular vascular effects of VEGF antagonists are still unclear. Costa et al evaluated the safety of intravitreal bevacizumab injections for the management of macular edema due to ischemic central or hemicentral retinal vein occlusion, with no complications noted at the 25-week follow-up in seven patients.Citation49 Neubauer et al tried to assess peripheral perfusion before and after intravitreal bevacizumab and described a significant improvement in retinal perfusion post injection in 19 patients with nonproliferative diabetic macular edema.Citation9 Chung et al found no visual improvement in eyes with diabetic macular ischemia after intravitreal bevacizumab, and no worsening of macular ischemia was found (pers comm; Koh HJ, March 2010).Citation50
Evidence suggests that vessel diameter is influenced by the drug.Citation51–Citation53 Retinal arteriolar diameter decreased by 4.6% ± 4.6% at day 7 and by 8.1% ± 3.2% at day 30 in eleven eyes with neovascular macular degeneration after treatment with intravitreal ranibizumab.Citation51 Similarly, 1 month after ranibizumab was injected into ten eyes with macular degeneration, Mendrinos et al found a mean arterial vasoconstriction of 8.4% ± 3.2%.Citation52 Sacu et al found significant retinal arterial and venous vasoconstriction with a significant reduction in retinal perfusion in 27 patients with retinal branch vein occlusion.Citation53 Soliman et al used bevacizumab to treat ten eyes with diffuse diabetic macular edema, and found that the most pronounced changes in vessel diameter occurred in two patients with proliferative diabetic retinopathy.Citation3 We measured a higher vasoconstrictor effect and some eyes had marked vasoconstriction. It is also possible that there is a shift from vessel dilation driven by ischemia to constriction induced by VEGF antagonists, hence the large constrictive response which is reported.
Treatment with intravitreal VEGF antagonists is accompanied by exacerbation of systemic hypertensionCitation54 and attenuation of systemic VEGF levels.Citation55 This effect on the vascular tone may last for 3 weeks following intravitreal injections,Citation54–Citation56 but Lee et al found that only 30-minute systolic values were significantly higher than baseline blood pressure after bevacizumab injection.Citation56 It is possible that this acute rise in blood pressure may be related to the stress of the intravitreal injection. Some patients have a panic attack during the injection, others get hyperglycemia,Citation57 while a few may develop a dendritic corneal ulcer following treatment.Citation58
Transient ocular hypertension after intravitreal injection of VEGF antagonists has been emphasized in many studies.Citation59–Citation62 Persistent ocular hypertension is of recent concern and occurs in around 3.4% of eyes, usually following multiple injections.Citation62 This may relate to the presence of silicone oil or other large particulate matter in the syringe, such as high molecular weight aggregates in repackaged bevacizumab. A considerable short-term rise in intraocular pressure occurs preferentially in hyperopic eyesCitation60,Citation62 and eyes with known glaucoma, so there is a need to monitor intraocular pressure and retinal perfusion especially in eyes with poor retinal circulation.Citation18 Acute angle closure glaucoma may also be precipitated by intravitreal injections.Citation62
The risk of ocular vascular events during anti-VEGF therapy was 0.108% in the treatments considered in the current study. The low rate and the large variation in the occurrence of such events among the collaborating centers may be related to several factors including the retrospective nature of the study, the ocular pathology bias, the natural history of ocular disease, and the absence of precisely scheduled fluorescein angiographic studies. Performing detailed eye examinations with fundus photography and fluorescein angiography initially, at 1 week, and 1 month post-injection in a prospective setting (such as in the prospective study from Mansoura University) yielded higher rates of ocular events than were reported following retrospective quick screening examinations at the time of repeated injections. Many of the reported events were asymptomatic, such as capillary occlusion outside the fovea, and minor branch retinal artery or vein occlusion. In the RESOLVE study, a total of 102 cases having ranibizumab injections for diabetic maculopathy resulted in two cases with retinal vascular events (capillary and arterial occlusions).Citation30 In the ROCC study, one of the 16 patients with central retinal vein occlusion developed central retinal artery occlusion.Citation63 Branch retinal artery occurred in one out of twelve consecutive patients with proliferative diabetic retinopathy following intravitreal bevacizumab.Citation32 In the ANCHORCitation64 and MARINACitation65 studies (280 and 477 patients, respectively), no retinal vascular events were noted after 2 years of repeated intravitreal ranibizumab for the wet form of age-related macular degeneration. Prior prospective studies and the current survey found that eyes with wet age-related macular degeneration had the lowest frequencies of vascular events (0%–0.3%)Citation5,Citation65 while eyes with a greater number of ischemic vascular diseases such as proliferative diabetic retinopathy yielded a higher frequency of retinal vascular events (2%–19%, as in the current prospective study).Citation30 The occurrence of ocular vascular occlusions after anti-VEGF medications was 2.61% in the diabetic population ( and ), almost 24 times the occurrence in the general population receiving VEGF antagonists ( and ).
Three studies show choroidal or retinal vaso-occlusion after intravitreal bevacizumab injections in experimental animals. Peters et al analyzed the acute intravitreal effects of bevacizumab in four cynomolgus monkeys and found that choriocapillaris endothelial cell fenestrations were significantly reduced, and that densely packed thrombocytes and leukocytes regionally occluded the choriocapillaris lumen of treated eyes.Citation66 Schraermeyer et al found that bevacizumab immune complexes activate platelets and cause thrombosis in choroidal vessels of primate eyes.Citation67,Citation68 Ameri et al evaluated the effects of intravitreal bevacizumab in a rabbit retinal neovascularization model. An intravitreal VEGF injection was administered and intravitreal bevacizumab was then injected at day 2 and at week 1, and it was found that administration of intravitreal bevacizumab at week 1 resulted in severe capillary nonperfusion at week 2.Citation69 Bonnin et al demonstrated ocular hypoperfusion after intravitreal bevacizumab in humans. In 15 patients with wet age-related macular degeneration, mean blood flow velocities were measured by ultrasound imaging before, and 4 weeks after, a single intravitreal injection of bevacizumab. Velocities decreased significantly in the central retinal, temporal posterior ciliary, and ophthalmic arteries by 10%, 20%, and 20% respectively.Citation60,Citation70 Sacu et al found significant vasoconstriction of retinal arteries and veins outside the area of nonischemic retinal branch vein occlusions as well as a significant reduction in the flow velocity of the retrobulbar central retinal artery.Citation53
The vascular events reported during VEGF antagonist therapies could be part of the natural history of the underlying ocular disease. A rise in blood pressure, stress of the procedure, the underlying systemic disease, and a sharp rise in intraocular pressure are variables that can be involved in some cases of ocular vascular events, and these variables can be detected and treated. A majority of the patients discussed in the current study had systemic diseases, particularly diabetes mellitus. VEGF antagonism could play a leader role in some cases that demonstrated vasoconstriction by analysis of vessel caliber. VEGF acts as a vessel dilator by stimulating nitric oxide synthesis, and influences the autoregulation in the microcirculation. If we block this rescuer, the retina may be damaged due to decreased retinal perfusion in the presence of a low ophthalmic systolic pressure. Because retinal vessel diameter is a useful surrogate for retinal perfusion, changes in the diameter of the retinal arterioles may indicate changes in retinal capillary blood flow. Thus, these findings suggest that VEGF antagonists may reduce retinal capillary blood flow, and caution should be exercised in the use of intravitreal VEGF inhibitors in eyes with severe ocular ischemia such as ocular ischemic syndrome with low ophthalmic systolic pressure or severe proliferative diabetic retinopathy.Citation11,Citation15 Further studies are needed to evaluate the incidence of vascular events during VEGF antagonist therapy in such high-risk patients.Citation11
Acknowledgments
The Collaborative Anti-VEGF Ocular Vascular Complications Group: K Bailey Freund, Ninel Z Gregori, Nikolaus Feucht, Alay Banker, Therese von Hanno, Claudio Furino, Sabine Aisenbrey, Wael Soliman, Rong-Kung Tsai, Hamid Hosseini, Eric Chen, Hee-Seung Chin, Jane Y Huang, Ali A Bodla, Ozgur Artunay, Vladimir Poposki, Daniel Vilaplana, Michael Larsen, M Tariq Bhatti, Hana A Mansour, Ihab Saab, Hasan Shahine, Zohar Yehoshua, Kara Dellatorre, Shree Kurup.
The authors acknowledge the contribution of Professor FT Fraunfelder who supplied the data from the National Registry of Drug-Induced Ocular Side Effects.
Disclosure
The authors have no financial interests in any product mentioned in the manuscript.
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