What is the evidence for systemic effects of intravitreal anti-VEGF agents, and should we be concerned?

Avery, Robert L.

doi:10.1136/bjophthalmol-2013-303844

Cited by 68 publications

(63 citation statements)

References 31 publications

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“…Prolonged suppression of plasma VEGF levels resulting from serial intravitreal anti-VEGF injections might, therefore, raise concern for unwanted systemic effects (Avery 2014). Thus, this study was to prospectively evaluate the effects on systemic VEGF levels after an intravitreal injection of aflibercept or ranibizumab.…”

Section: Introductionmentioning

confidence: 99%

Systemic levels of vascular endothelial growth factor before and after intravitreal injection of aflibercept or ranibizumab in patients with age‐related macular degeneration: a randomised, prospective trial

Zehetner

Kralinger

Modi

et al. 2014

Acta Ophthalmologica

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ABSTRACT.Purpose: To evaluate the changes of vascular endothelial growth factor (VEGF) plasma levels after intravitreal injections of aflibercept or ranibizumab in patients with exudative age-related macular degeneration (AMD). Methods: Thirty-eight patients with exudative AMD were included in this randomised, prospective study. Nineteen patients were randomised to treatment with intravitreal aflibercept (2.0 mg) and 19 to intravitreal ranibizumab (0.5 mg). The concentration of VEGF was measured by ELISA just before the injection, after 7 days and 1 month. Twenty-two age-and sex-matched healthy patients without chorioretinal diseases served as control. Results: The median baseline plasma VEGF concentration was 61.0 pg/ml in the control group, 43.0 pg/ml in the aflibercept group and 59.0 pg/ml in the ranibizumab group (p = 0.127). Seven days after intravitreal injection of aflibercept plasma levels were significantly reduced to values below the minimum detectable dose (MDD) in 17 of 19 patients (89.5%) resulting in a median VEGF concentration of <9 pg/ml (p < 0.001). The reduction persisted throughout 1 month with values below the MDD in 5 of 19 patients (26.3%) and a median measurement of 17.0 pg/ml (p < 0.001). In patients treated with ranibizumab no significant effects could be observed with a baseline VEGF of 59.0 pg/ml, 54.0 pg/ ml at 7 days (p = 0.776) and 58.5 pg/ml at 4 weeks of follow-up (p = 0.670). Conclusion: After intravitreal aflibercept injection, the systemic VEGF levels were significantly reduced throughout the observational period of 4 weeks. No significant systemic effects of intravitreal ranibizumab on plasma VEGF were observed.

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Section: Introductionmentioning

confidence: 99%

Systemic levels of vascular endothelial growth factor before and after intravitreal injection of aflibercept or ranibizumab in patients with age‐related macular degeneration: a randomised, prospective trial

Zehetner

Kralinger

Modi

et al. 2014

Acta Ophthalmologica

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“…Although intravitreal anti-VEGF treatment is generally believed to be systemically safe, it has been difficult to determine whether anti-VEGF might increase the risk of stroke, arteriothrombotic events, or cardiovascular events because studies have been underpowered and patients with DME may be at increased risk of these events regardless of treatment. 46 However, the majority of panelists agreed that they typically would likely consider a change in therapy if a patient being treated with anti-VEGF had a recent stroke or cardiovascular event. In a recent meta-analysis that pooled systemic safety data from patients treated with ranibizumab 0.5 mg or aflibercept in clinical studies, the risk of cerebrovascular accidents and vascular deaths was significantly higher in patients treated monthly for 2 years with anti-VEGF injections than in patients treated with sham, 47 suggesting that frequent anti-VEGF injections over the long term may increase the risk of serious systemic adverse events.…”

Section: Discussionmentioning

confidence: 99%

Use of Corticosteroids in the Treatment of Patients With Diabetic Macular Edema Who Have a Suboptimal Response to Anti-VEGF: Recommendations of an Expert Panel

Regillo¹,

Callanan²,

Diana³

et al. 2017

Ophthalmic Surg Lasers Imaging Retina

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BACKGROUND AND OBJECTIVE: Guidance on the use of corticosteroids in the treatment of diabetic macular edema (DME) is lacking. This study aimed to develop a clinically recommended treatment paradigm for DME with emphasis on the role of corticosteroids. PATIENTS AND METHODS: An expert panel of nine retinal specialists in the United States developed consensus recommendations for DME treatment through a modified Delphi process. RESULTS: The panelists typically use intravitreal injections of vascular endothelial growth factor (VEGF) antagonists as first-line treatment of DME and switch patients with an inadequate response to anti-VEGF therapy (failure of best-corrected visual acuity to improve to 20/40 or better because of edema after three to six monthly injections, or a less-than-50% reduction in excess macular thickness after three to four monthly injections) to intravitreal corticosteroid treatment. CONCLUSION: Intravitreal corticosteroids have a potentially useful role in the treatment of patients with DME who have an inadequate response to intravitreal anti-VEGF therapy. [ Ophthalmic Surg Lasers Imaging Retina. 2017;48:291–301.]

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“…1 However, VEGF is one of the most potent cytokines and has an essential role in angiogenesis, giving it an important role in the normal development of the brain, lung, and kidney tissue in children, 2 as well as in maintaining normal organ function in adults. [3][4][5] However, the effects of intraocular administration of anti-VEGF drugs on systemic levels remain controversial.…”

Section: Introductionmentioning

confidence: 99%

“…[3][4][5] However, the effects of intraocular administration of anti-VEGF drugs on systemic levels remain controversial. 1 Different anti-VEGF agents also have different molecular structures, different transmissibility across the blood-retinal barrier, and different systemic half-lives, so could potentially have different effects on systemic VEGF levels. 1,[6][7][8][9] Ranibizumab is a recombinantly produced, humanized monoclonal antibody fragment (Fab) designed for intraocular use that binds and inhibits all biologically active isoforms of human VEGF.…”

Section: Introductionmentioning

confidence: 99%

“…1 Different anti-VEGF agents also have different molecular structures, different transmissibility across the blood-retinal barrier, and different systemic half-lives, so could potentially have different effects on systemic VEGF levels. 1,[6][7][8][9] Ranibizumab is a recombinantly produced, humanized monoclonal antibody fragment (Fab) designed for intraocular use that binds and inhibits all biologically active isoforms of human VEGF. 10 Its transmissibility across the blood-retinal barrier is lower than that of fulllength molecules, but systemic bioavailability of ranibizumab has been reported post intravitreal injections.…”

Section: Introductionmentioning

confidence: 99%

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Multiphasic changes in systemic VEGF following intravitreal injections of ranibizumab in a child

Shao

Sivagnanavel

Dabbagh

et al. 2015

Eye

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Purpose To investigate whether intravitreal ranibizumab injections administered to a child alter systemic plasma levels of total and free VEGF 165. Methods A 9-year-old child sustained a choroidal rupture from blunt trauma. He subsequently developed a secondary choroidal neovascular membrane, which was treated with five ranibizumab injections over a period of 8 months. Peripheral venous blood samples were taken at each visit over a period of 12 months and plasma was extracted. Plasma VEGF 165 levels were determined using enzyme-linked immunosorbent assay and were assayed both pre-and post-immunodepletion to remove complexed VEGF. Results Plasma VEGF 165 levels proved labile following intravitreal injection of ranibizumab. Levels increased by 30% above baseline following the first intravitreal ranibizumab injection, but then returned to baseline despite two subsequent injections. There was then a rebound increase of 67% in total plasma VEGF levels following a further injection, which remained above baseline for 12 weeks despite two further intravitreal ranibizumab injections. Baseline levels were re-attained 26 weeks after the final injection. Conclusions These results suggest intravitreal ranibizumab injections can cause significant, multiphasic changes in systemic VEGF levels. This may be of particular clinical significance in children as VEGF is known to be vital in the development of major organs, in addition to its role in the maintenance of normal organ function in adults.

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What is the evidence for systemic effects of intravitreal anti-VEGF agents, and should we be concerned?

Cited by 68 publications

References 31 publications

Systemic levels of vascular endothelial growth factor before and after intravitreal injection of aflibercept or ranibizumab in patients with age‐related macular degeneration: a randomised, prospective trial

Systemic levels of vascular endothelial growth factor before and after intravitreal injection of aflibercept or ranibizumab in patients with age‐related macular degeneration: a randomised, prospective trial

Use of Corticosteroids in the Treatment of Patients With Diabetic Macular Edema Who Have a Suboptimal Response to Anti-VEGF: Recommendations of an Expert Panel

Multiphasic changes in systemic VEGF following intravitreal injections of ranibizumab in a child

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